m6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer.

N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, and then validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11 transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.

A teenage girl with cystic fibrosis-related diabetes, diabetic ketoacidosis, and cerebral edema.

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes, most commonly associated with type 1 diabetes. Here, we report the case of a 17-yr-old girl with cystic fibrosis and a prior diagnosis of cystic fibrosis-related diabetes (CFRD) who presented with DKA in the setting of insulin omission and glucocorticoid use. During the course of treatment for DKA, her neurologic status declined and head computerized tomography confirmed cerebral edema. Recognition of DKA and cerebral edema allowed for timely treatment, and the patient recovered without sequelae. This is the first report of DKA complicated by cerebral edema that is attributable to CFRD.