Key Points Question Are thyroid disorders associated with colorectal cancer risk in an East Asian population? Findings In this case-control study that included 139 426 adults in Taiwan with or without a diagnosis of primary colorectal cancer, both hyperthyroidism and hypothyroidism appeared to be associated with a statistically significantly decreased risk of colorectal cancer diagnosis. Meaning Given these findings, it appears that biochemical in vivo research and epidemiologic studies are needed to further clarify the nature of the association found between thyroid disease and colorectal cancer and may potentially advance the therapies for colorectal cancer.

Physicochemical principles such as stoichiometry and fractal assembly can give rise to characteristic scaling between components that potentially include coexpressed transcripts. For key structural factors within the nucleus and extracellular matrix, we discover specific gene-gene scaling exponents across many of the 32 tumor types in The Cancer Genome Atlas, and we demonstrate utility in predicting patient survival as well as scaling-informed machine learning (SIML). All tumors with adjacent tissue data show cancer-elevated proliferation genes, with some genes scaling with the nuclear filament LMNB1, including the transcription factor FOXM1 that we show directly regulates LMNB1. SIML shows that such regulated cancers cluster together with longer overall survival than dysregulated cancers, but high LMNB1 and FOXM1 in half of regulated cancers surprisingly predict poor survival, including for liver cancer. COL1A1 is also studied because it too increases in tumors, and a pan-cancer set of fibrosis genes shows substoichiometric scaling with COL1A1 but predicts patient outcome only for liver cancer—unexpectedly being prosurvival. Single-cell RNA-seq data show nontrivial scaling consistent with power laws from bulk RNA and protein analyses, and SIML segregates synthetic from contractile cancer fibroblasts. Our scaling approach thus yields fundamentals-based power laws relatable to survival, gene function, and experiments.

Ewing sarcoma is driven by fusion proteins containing a low-complexity (LC) domain that is intrinsically disordered and a powerful transcriptional regulator. The most common fusion protein found in Ewing sarcoma, EWS-FLI1, takes its LC domain from the RNA-binding protein EWSR1 (Ewing sarcoma RNA-binding protein 1) and a DNA-binding domain from the transcription factor FLI1 (Friend leukemia virus integration 1). EWS-FLI1 can bind RNA polymerase II (RNA Pol II) and self-assemble through its LC domain. The ability of RNA-binding proteins like EWSR1 to self-assemble or phase separate in cells has raised questions about the contribution of this process to EWS-FLI1 activity. We examined EWSR1 and EWS-FLI1 activity in Ewing sarcoma cells by siRNA-mediated knockdown and RNA-seq analysis. More transcripts were affected by the EWSR1 knockdown than expected and these included many EWS-FLI1 regulated genes. We reevaluated physical interactions between EWS-FLI1, EWSR1, and RNA Pol II, and used a cross-linking-based strategy to investigate protein assemblies associated with the proteins. The LC domain of EWS-FLI1 was required for the assemblies observed to form in cells. These results offer new insights into a protein assembly that may enable EWS-FLI1 to bind its wide network of protein partners and contribute to regulation of gene expression in Ewing sarcoma.

Background and ObjectivesDementia has been gaining attention in aging societies and is estimated to affect 50 million adults globally in 2020, and 12% of the US population may develop a thyroid disorder in their lifetime. There have been limited studies investigating the correlation between thyroid disorder and dementia in the Asian population.MethodsOur large nationwide population-based case-control study used the Taiwanese National Health Insurance Research Database. A total of 7,843 adults with newly diagnosed dementia without a history of dementia or neurodegenerative disease between 2006 and 2013 were identified and included in our study. In addition, 7,843 adults without dementia diagnosis before the index date were age and sex-matched as controls. Diagnosis of hyperthyroidism or hypothyroidism before the diagnosis of dementia or the same index date was identified. Results were obtained from logistic regression models and adjusted for sex, age, history of hypertension, diabetes, coronary artery disease, depression, hyperlipidemia, alcohol dependence syndrome, tinnitus, hearing loss, and radioactive iodine treatment.ResultsA total of 15,686 patients were included in the study. Both case and control groups were slightly predominantly female (4,066 [51.8%]). The mean (SD) age for those with dementia was 74.9 (11.3) years and for those without dementia was 74.5 (11.3) years. Among patients aged 65 years or older, a history of hypothyroidism was associated with an increased risk of being diagnosed with dementia (adjusted odds ratio [aOR] 1.81; 95% CI 1.14–2.87; p = 0.011), which was an association not present in patients older than 50 years but younger than 65 years. We found that this association was most significant among patients aged 65 years or older with a history of hypothyroidism who received hypothyroidism medication (aOR 3.17; 95% CI 1.04–9.69; p = 0.043).DiscussionOur large-scale case-control study found that among people aged 65 years or older, those with a history of hypothyroidism were associated with an 81% increased risk of having dementia and among those, there was a more than 3-fold increased dementia risk with thyroid conditions that required thyroid hormone replacement treatment. Future well-controlled prospective longitudinal studies should be conducted to elucidate these potential mechanisms and relationships.Classification of EvidenceThis study provides Class III evidence that among patients aged 65 years or older, a history of hypothyroidism was associated with an increased risk of being diagnosed with dementia.