Acquired deficiency of peroxisomal dicarboxylic acid catabolism is a metabolic vulnerability in hepatoblastoma.

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 ß- 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.

Hand Dexterity Is Associated with the Ability to Resolve Perceptual and Cognitive Interference in Older Adults: Pilot Study.

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.

Neural correlates of the sound facilitation effect in the modified Simon task in older adults.

Introduction: The ability to resolve interference declines with age and is attributed to neurodegeneration and reduced cognitive function and mental alertness in older adults. Our previous study revealed that task-irrelevant but environmentally meaningful sounds improve performance on the modified Simon task in older adults. However, little is known about neural correlates of this sound facilitation effect. Methods: Twenty right-handed older adults [mean age = 72 (SD = 4), 11 female] participated in the fMRI study. They performed the modified Simon task in which the arrows were presented either in the locations matching the arrow direction (congruent trials) or in the locations mismatching the arrow direction (incongruent trials). A total of 50% of all trials were accompanied by task-irrelevant but environmentally meaningful sounds. Results: Participants were faster on the trials with concurrent sounds, independently of whether trials were congruent or incongruent. The sound effect was associated with activation in the distributed network of auditory, posterior parietal, frontal, and limbic brain regions. The magnitude of the behavioral facilitation effect due to sound was associated with the changes in activation of the bilateral auditory cortex, cuneal cortex, and occipital fusiform gyrus, precuneus, left superior parietal lobule (SPL) for No Sound vs. Sound trials. These changes were associated with the corresponding changes in reaction time (RT). Older adults with a recent history of falls showed greater activation in the left SPL than those without falls history. Conclusion: Our findings are consistent with the dedifferentiation hypothesis of cognitive aging. The facilitatory effect of sound could be achieved through recruitment of excessive neural resources, which allows older adults to increase attention and mental alertness during task performance. Considering that the SPL is critical for integration of multisensory information, individuals with slower task responses and those with a history of falls may need to recruit this region more actively than individuals with faster responses and those without a fall history to overcome increased difficulty with interference resolution. Future studies should examine the relationship among activation in the SPL, the effect of sound, and falls history in the individuals who are at heightened risk of falls.

Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas.

BACKGROUND & AIMS: Hepatoblastoma (HB), the most common pediatric liver cancer, often bears ß-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing ß-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis. METHODS: We evaluated NFE2L2's role in HB pathogenesis by co-expressing all combinations of mutant ß-catenin, YAPS127A, and the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles, and transcriptomes of the ensuing tumors. RESULTS: In association with ß-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any 2 members of the mutant ß-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2's oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth, and extracellular matrix. Although the combination of mutant ß-catenin, YAPS127A, and serpin E1 did not accelerate cystogenic tumor growth, it did promote the widespread necrosis associated with mutant ß-catenin-YAPS127A-L30P/R34P tumors. CONCLUSIONS: Our findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.