C/EBPß regulates the M2 transcriptome in ß-adrenergic-stimulated macrophages.

At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBPß. Signaling through ß-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBPß regulates the signaling pathway between ß-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. ß-adrenergic signaling induced Cebpb gene expression relatively early with a peak at 1 h post-stimulation, followed by peak Arg1 gene expression at 8 h. C/EBPß transcription factor activity was elevated at the enhancer region for Arg 1 at both 4 and 8 h after stimulation but not near the more proximal promoter region. Knockdown of Cebpb suppressed the ß-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBPß protein in the nucleus, which resulted in suppression of ß-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by ß-adrenergic- and C/EBPß-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBPß transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of ß-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.

Hepatocellular carcinoma in Pacific Islanders: comparison of Pacific Island-born vs. US-born.

Aim: To describe demographic, clinical, and outcome differences in Pacific Island-born (PI-born) compared to US-born hepatocellular carcinoma (HCC) patients of Pacific Island ancestry within a clinical cohort in Hawaii. Methods: A prospectively collected database of 1608 patients diagnosed with HCC over a 30-year period (1993-2022) identified 252 patients of Pacific Islander ethnicity. Data collected: demographics, medical history, laboratory data, tumor characteristics, treatment, and survival. Patients were divided into two groups: PI-born and US-born. Categorical variables were analyzed using ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated using univariate and multivariate logistic regression. Overall survival was evaluated using Kaplan-Meier analysis. Results: PI-born patients were younger (57.3 vs. 61.8 years, P = 0.002) and more likely to have hepatitis B (OR 14.10, 7.50-26.50) and underlying cirrhosis (OR 2.28, 1.17-4.45). In comparison, US-born patients had a significantly higher likelihood of Hepatitis C, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, history of non-HCC cancer, and positive smoking history compared to PI-born patients. PI-born patients were more likely to forego treatment (OR 3.22, 1.77-5.87) and be lost to follow-up (OR 9.21, 1.97-43.03). Both groups were equally likely to have the opportunity for curative surgical treatment (liver resection or transplant). US-born status was associated with higher mortality risk, while transplantation was associated with lower mortality risk. The PI-born cohort demonstrated higher overall survival at 3 and 5 years compared to US-born. Conclusion: HBV remains the primary risk factor for HCC in PI-born patients, whereas HCC in US-born patients is more associated with the adoption of a Westernized lifestyle.

Vasoactive Intestinal Peptide-Secreting Pheochromocytoma: A Case Report and Review of Literature.

Objective: To describe a case of composite vasoactive intestinal peptide (VIP)-secreting pheochromocytoma and review literature to provide insight into the various presentations and potential management of these rare tumors. Case Report: A 64-year-old male patient presented with hypertensive emergency and coronary demand ischemia with development of watery diarrhea, hypokalemia, and achlorhydria syndrome. Serum and urine studies demonstrated elevated metanephrine and VIP levels. Definitive surgical resection resolved symptoms and normalized laboratory values. Pathologic examination of the specimen revealed pheochromocytoma with a Pheochromocytoma of the Adrenal gland Scaled Score of 4 and patchy expression of VIP. Discussion: Given the different actions of hormones that can be secreted by these composite tumors, we suggest that pheochromocytomas with diversified secretory capabilities may be an underrecognized clinical entity. Localized disease is often amenable to surgical resection, although management of metastatic disease is not well established due to the rarity of these tumors and lack of randomized trials. Conclusion: In patients presenting with diarrhea of unclear etiology or the suggestion of secondary hypertension, assessment for a possible neuroendocrine tumor may be prudent. If an adrenal mass is discovered but the patient exhibits atypical symptoms of catecholamine excess, a diagnosis of composite pheochromocytoma with multisecretory properties should be considered.