The pediatric liver cancer hepatoblastoma (HB) often expresses mutant forms of β-catenin and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing these β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other human cancers also express mutant forms of NFE2L2/NRF2 (NFE2L2), a bHLH transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis in a context- and time-dependent manner. We show here that two patient-derived NFE2L2 missense mutants, L30P and R34P, markedly accelerate HB growth in association with widespread cyst formation, an otherwise uncommon feature of human HB. Surprisingly, we found that any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus providing direct evidence for NFE2L2's role as an oncoprotein. Each tumor group displayed distinct features but shared a similarly deregulated set of 22 transcripts, 10 of which perfectly correlated with survival in human HBs. 17 transcripts also correlated with survival in multiple other adult cancers. One of the most highly deregulated transcripts encoded serpin E1, a serine protease inhibitor with roles in fibrinolysis, tumor growth and extracellular matrix formation. The combination of mutant β-catenin, YAPS127A and Serpin E1, while not accelerating tumor growth or generating cysts, did promote the wide-spread necrosis previously associated with the cysts of mutant β-catenin-YAPS127A-L30P/R34P tumors. These findings establish the direct oncogenicity of NFE2L2 mutants and identify key transcripts, including serpin E1, that drive specific HB features.
The relationship between hand dexterity and inhibitory control across the lifespan is underexplored. In this pilot study, we examined inhibitory control using a modified Simon task. During the task, participants were presented with right- and left-pointing arrows located either on the right or the left parts of the screen. In the congruent trials, the arrow location and direction matched. In the incongruent trials, they mismatched, thus creating cognitive interference. In 50% of trials, the arrow presentation was accompanied by a task-irrelevant but environmentally meaningful sound that created perceptual interference. Hand dexterity was measured with the 9-hole peg test. Significantly faster reaction time (RT) on the modified Simon task (p < 0.001) was observed in younger adults, trials with concurrent sound stimuli, and congruent trials. Older adults who reported recent falls had greater difficulty resolving cognitive interference than older adults without recent falls. Hand dexterity significantly moderated the effect of sound on RT, but only in the group of older individuals. Interestingly, older individuals with reduced hand dexterity benefited from concurrent sounds more than those with better hand dexterity. Our findings suggest that task-irrelevant but environmentally meaningful sounds may increase alertness and enhance stimulus perception and recognition, thus improving motor performance in older individuals.
Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. Capitalizing on this therapeutically, however, has been only moderately successful because of the relatively small magnitude of these differences and because cancers may further adapt their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bifunctional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate the toxic metabolite dodecanedioic acid (DDDA), which causes acute hepatocyte necrosis and liver failure. We noted that, in a murine model of pediatric hepatoblastoma (HB) and in primary human HBs, downregulation of Ehhadh occurs in association with the suppression of mitochondrial β- and endosomal/peroxisomal ω-fatty acid oxidation pathways. This suggested that HBs might be more susceptible than normal liver tissue to C12 dietary intervention. Indeed, HB-bearing mice provided with C12- and/or DDDA-supplemented diets survived significantly longer than those on standard diets. In addition, larger tumors developed massive necrosis following short-term DDDA administration. In some HBs, the eventual development of DDDA resistance was associated with 129 transcript differences, ∼90% of which were downregulated, and approximately two-thirds of which correlated with survival in numerous human cancers. These transcripts often encoded extracellular matrix components, suggesting that DDDA resistance arises from reduced Ehhadh uptake. Lower Ehhadh expression was also noted in murine hepatocellular carcinomas and in subsets of certain human cancers, supporting the likely generality of these results. Our results demonstrate the feasibility of C12 or DDDA dietary supplementation that is nontoxic, inexpensive, and likely compatible with more standard chemotherapies.
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