Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.

Targeting the GTV in medically inoperable endometrial cancer using brachytherapy.

PURPOSE: We aimed to determine the relationship between gross tumor volume (GTV) dose and tumor control in women with medically inoperable endometrial cancer, and to demonstrate the feasibility of targeting a GTV-focused volume using imaged-guided brachytherapy. METHODS AND MATERIALS: An endometrial cancer database was used to identify patients. Treatment plans were reviewed to determine doses to GTV, clinical target volume (CTV), and OARs. Uterine recurrence-free survival was evaluated as a function of CTV and GTV doses. Brachytherapy was replanned with a goal of GTV D98 EQD2 ≥ 80 Gy, without regard for coverage of the uninvolved uterus and while respecting OAR dose constraints. RESULTS: Fifty-four patients were identified. In the delivered plans, GTV D90 EQD2 ≥ 80 Gy was achieved in 36 (81.8%) patients. Uterine recurrence-free survival was 100% in patients with GTV D90 EQD2 ≥ 80 Gy and 66.7% in patients with EQD2 < 80 Gy (p = 0.001). On GTV-only replans, GTV D98 EQD2 ≥ 80 Gy was achieved in 39 (88.6%) patients. Mean D2cc was lower for bladder (47.1 Gy vs. 73.0 Gy, p < 0.001), and sigmoid (47.0 Gy vs. 58.0 Gy, p = 0.007) on GTV-only replans compared to delivered plans. Bladder D2cc was ≥ 80 Gy in 11 (25.0%) delivered plans and four (9.1%) GTV-only replans (p = 0.043). Sigmoid D2cc was ≥ 65 Gy in 20 (45.4%) delivered plans and 10 (22.7%) GTV-only replans (p = 0.021). CONCLUSIONS: OAR dose constraints should be prioritized over CTV coverage if GTV coverage is sufficient. Prospective evaluation of image-guided brachytherapy to a reduced, GTV-focused volume is warranted.