Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death.

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.

Prevalence and implications of perinephric fluid on renal point-of-care ultrasound in the emergency department.

BACKGROUND: Point-of-care ultrasound (PoCUS) is commonly utilized in the setting of renal colic. The presence of perinephric fluid may be an overlooked finding associated with ureteral obstruction. Our aims were to determine the prevalence of perinephric fluid on emergency physician-performed PoCUS and to determine whether perinephric fluid was associated with stone size or urologic intervention. METHODS: This was a 12-month cross-sectional study at an academic emergency department (ED) that took place from January 1, 2022, to December 31, 2022. All adult ED patients ≥18 years of age who had a renal PoCUS examination performed were included. Patients with missing or inadequate PoCUS images were excluded. Investigators blinded to PoCUS images and interpretations performed chart review for demographic data and outcome variables, while separate investigators blinded to clinical data reviewed PoCUS images to assess for perinephric fluid and hydronephrosis. A chi-square analysis was used to determine significance of association between perinephric fluid and outcome variables (stone size, urologic intervention). RESULTS: There were 442 patients screened; 18 were excluded due to inadequate images and 4 were repeat visits of which only the initial visit was analyzed. Of the remaining 420 patients included, the prevalence of perinephric fluid was 6.2% (n = 26). Most patients (23/26) with perinephric fluid had final diagnoses consistent with ureterolithiasis. Hydronephrosis was present in 115 of the 420 patients (27.4%) and of these, 22 (19.1%) had perinephric fluid which was significantly associated with a need for urologic intervention; odds ratio (OR) 10.38 (95% CI 2.70-39.85), p < 0.01. Among the 67 patients with confirmed ureterolithiasis on computed tomography, perinephric fluid was associated with stone size ≥5 mm; OR 4.00 (95% CI 1.01-15.85), p = 0.04. CONCLUSION: The prevalence of perinephric fluid on emergency physician-performed renal PoCUS was 6.2% of all studies and 19.1% of patients with hydronephrosis. In the setting of ureterolithiasis, perinephric fluid was associated with larger stone size and need for urologic intervention.

ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia.

Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-ß (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.