Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the “aging” Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.

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Background The objective of this study was to evaluate whether sex- and gender-based analyses and proper sex- and gender-terminology were used in oncology trials leading to regulatory drug approval. Methods The Food and Drug Administration (FDA) Hematology/Oncology Approvals and Safety Notifications page was used to identify all anti-cancer therapies that received FDA approval between 2012 and 2019. The trials used to support FDA-drug approval were collected along with all available supplemental tables and study protocols. Documents were reviewed to determine if there was a plan to analyze results according to sex and gender and to determine if consistent sex and gender terminology were used. Results 128 randomized-controlled trials were identified corresponding to a cancer medicine which received FDA-approval. No study specified how sex and gender were collected or analyzed. No study reported any information on the gender of participants. Sex and gender terminology was used inconsistently at least once in 76% (97/128) of studies. Among the 102 trials for non-sex-specific cancer sites, 89% (91/102) presented disaggregated survival outcome data by sex. No study presented disaggregated toxicity data by sex or gender. Conclusion The majority of pivotal clinical trials in oncology fail to account for the important distinction between sex and gender and conflate sex and gender terminology. More rigor in designing clinical trials to include sex and gender based analyses and more care in using sex and gender terms in the cancer literature is needed. These efforts are essential to improve the reproducibility, generalizability, and inclusiveness of cancer research.

The curly tail (ct\ct) mouse mutant shows a high frequency of delay or failure of neural tube closure, and is a good model for human neural tube defects, particularly spina bifida. In a previous study we defined distinct domains of gene expression in the caudal region of non-mutant embryos during posterior (caudal) neuropore closure (Gofflot et al. Developmental Dynamics 210, 431-445, 1997). Here we use BrdU incorporation into S-phase nuclei to investigate the relationship between cell proliferation and the previously described gene expression domains in ct\ct mutant embryos. The BrdU-immunostained sections were also examined for abnormalities of tissue structure ; immunohistochemical detection of perlecan (an extracellular heparan sulphate proteoglycan) was used as an indicator of neuroepithelial basement membrane structure and function. Quantitation of BrdU uptake revealed that at early stages of neurulation, cell proliferation was specifically reduced in the paraxial mesoderm of all ct\ct embryos compared with wild type controls, but at later stages (more cranial levels) it was increased. Those ct\ct embryos with enlarged posterior neuropore (indicating delay of closure) additionally showed an increased BrdU labelling index within the open neuroepithelium at all axial levels ; however, this tissue was highly abnormal with respect to cell and nuclear morphology. It showed cell death and loss of cells from the apical surface, basement membrane defects including increased perlecan immunoreactivity, and increased separation from the underlying mesenchyme and notochord. These observations suggest that the mechanism of delay or failure of neuroepithelial curvature that leads to neural tube defects in curly tail embryos involves abnormalities of neuroepithelial-mesenchymal interactions that may be initiated by abnormal cellular function within the neuroepithelium. Minor histological and proliferation abnormalities are present in all ct\ct embryos, regardless of phenotype.

Shortening ends of mRNAs cooperate with oncogenes in development and cancer.

Alternative polyadenylation of pre-mRNA has been recently shown to play important roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers but the mechanisms by which they cooperate with alternative polyadenylation are not known. By exploiting the genetics of C. elegans, we identified cfim-1/CFIm25, a subunit of the alternative polyadenylation machine, as a key determinant of hyperactive Ras function. Ablation of cfim-1 increased penetrance of multivulva phenotype in let-60/Ras gain-of-function (gf) mutant through shortening of transcripts at the 3' untranslated region, including p21 activated kinase pak-1/PAK1 and multidrug transporter mrp-5/ABCC1. Depletion of CFIm25 in human KRAS-driven cancer cells resulted in a similar shortening of 3' untranslated regions in the PAK1 and ABCC1 transcripts, which caused an epithelial-to-mesenchymal transition and increased cell migration. Exploiting the mechanisms by which alternative polyadenylation affects activated oncogene output could offer novel approaches for the treatment of Ras-driven tumors.

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