Mechanisms of STAT3 activation in the liver of FXR knockout mice.

Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice.

Endoscopic techniques in resection of anterior skull base/paranasal sinus malignancies.

OBJECTIVE: The objective of this study was to examine the role of endoscopic approaches to the resection of anterior skull base and paranasal sinus malignancies at one tertiary care medical center. STUDY DESIGN: The authors conducted a retrospective chart review over a period of 17 years. METHODS: Patients undergoing anterior skull base resections for malignancies over a 17-year period were reviewed. Data were collected on each patient with respect to the pathology of the tumor and approach used as well as demographic and follow-up information. RESULTS: A total of 78 patients were treated at a tertiary care medical center for malignancies of the paranasal sinuses and anterior skull base. The most common diagnosis was squamous cell carcinoma occurring in 33% of the cases. The remaining pathologies included esthesioneuroblastoma (23%), adenoid cystic carcinoma (15%), melanoma (3%), sinonasal undifferentiated carcinoma (3%), lymphoma (5%), nasopharyngeal carcinoma (4%), and other tumor types (14%). Endoscopic techniques were used extensively in this population of patients. Combined approaches using a sublabial/transmaxillary approach and coronal approaches were used when indicated and complemented the endoscopic approach. A majority of patients were without evidence of disease at the end of this review. Using endoscopic techniques allowed for acceptable cosmetic results and facial incisions were used minimally. CONCLUSION: With complete endoscopic surgical resection followed by radiation therapy, local recurrence, morbidity, and cosmetic deformity have been minimized. The microscopic view provided by endoscopic techniques, with or without complementary approaches, allows for complete tumor removal.

Sex does not seem to influence the formation of aortic lesions in the P-407-induced mouse model of hyperlipidemia and atherosclerosis.

Coronary heart disease secondary to atherosclerosis is the leading cause of death for men in the United States. Using a new, nontransgenic, non-fat-fed mouse model of hyperlipidemia and atherosclerosis developed in our laboratory, we investigated the effect of sex on lipid profiles and subsequent aortic atherosclerotic lesion formation. Female and male C57BL/6 mice, which consumed a low-fat diet, were treated with either normal saline or poloxamer 407 (P-407), a triblock copolymer comprised of poly(oxyethylene) and poly(oxypropylene) units, for 4 months. Blood samples were obtained at 0, 1, 2, 3, and 4 months, whereas hearts and livers were harvested only at 4 months, because this model requires approximately 4 months for significant atheroma formation. P-407-treated mice of either sex demonstrated a profound increase in plasma cholesterol and triglyceride; at 3 and 4 months the plasma lipids were significantly (p < 0.05) higher for male mice compared with female mice. Aortas retrieved from P-407-treated mice of either sex after 4 months demonstrated a significant (p < 0.001) increase in the mean atherosclerotic lesion size compared with their respective saline-treated controls, but there was no significant (p > 0.05) difference between lesion sizes for P-407-treated male mice (1.02 +/- 0.074 x 10(5) microm(2)) compared with P-407-treated female mice (1.14 +/- 0.28 x 10(5) microm(2)). Livers harvested at 4 months from either sex of P-407-treated mice displayed no damage to hepatocytes but increased proliferation of macrophages (Kupffer cells), which contained sequestered lipids. Thus, male C57BL/6 mice form atherosclerotic lesions as extensive as female mice in the P-407 mouse model of atherosclerosis.