Hepatic encephalopathy (HE) is a serious neurological complication of acute and chronic liver failure. Expression of the neurosteroid/bile acid receptor TGR5 has been demonstrated in the brain and is thought to be neuroprotective. However, it is unknown how TGR5 signaling can influence the progression and associated neuroinflammation of HE. HE was induced in C57Bl/6 mice via intraperitoneal injection of azoxymethane (AOM) and tissue was collected throughout disease progression. TGR5 expression was elevated in the frontal cortex following AOM injection in mice. The cellular localization of TGR5 was found in both neurons and microglia in the cortex of C57Bl/6 mice. Central infusion of the TGR5 agonist, betulinic acid, prior to AOM injection delayed neurological decline, increased cortical cyclic adenosine monophosphate concentrations, reduced microglia activation and proliferation, and reduced proinflammatory cytokine production. Betulinic acid treatment in vitro reduced the neuronal expression of CCL2, a chemokine previously demonstrated to contribute to HE pathogenesis. Lastly, treatment of the microglia cell line EOC-20 with conditioned media from betulinic acid-treated primary neurons decreased phagocytic activity and cytokine production. Together, these data identify that activation of TGR5, which is upregulated during HE, alleviates neuroinflammation and improves outcomes of AOM-treated mice through neuron and microglia paracrine signaling.

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using pre-operative radiation therapy. Patients had to have an operable tumor and no evidence of distant metastases. The majority of the tumors were fairly extensive and displacing abdominal organs. All patients were treated with megavoltage radiation with IMRT delivery. A minimum dose of 45 Gy was delivered to full volume with a margin to the PTV. An SIB was delivered to the GTV or the high dose areas to a dose of 55 GY all in 25 Daily Fractions. Surgery followed 4-6 weeks later. Results: During the period of 2011 to 2014, 23 patient s have been treated. The use of IMRT has facilitated dose delivery and escalation in a safe manner. The patterns of toxicity including bowel symptoms and delayed healing have been compared with historical controls. None of our patient has developed any significant acute toxicity necessitating stopping radiation therapy. No severe late effects have been reported. Despite the large volume treatment surgical resections have been successful in all patients. Follow-up is ranging from 6 months to 4 years. Detailed toxicity analysis will be presented at the meeting. Conclusion: Dose escalation and dose delivery to a large abdominal volume are safe and feasible in RP Sarcomas with the use of IMRT. Acute and subacute side effects are limited and much less than historical controls. It remains to be seen if that will translate into long term improvement in survival.