Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.

Experimental rat models of simulated brachial plexus injuries were devised to compare the effect of contralateral C7 root transfer with phrenic neurotization. The effect of vascularized nerve grafting (VNG) was also compared with the use of conventional nerve grafts (CNG) in the treatment of root avulsion of the brachial plexus. 160 rats were randomly divided into four groups of 40 each; contralateral C7 root transfer with a vascularized ulnar nerve graft (C7-VNG), contralateral C7 root transfer with conventional ulnar nerve grafting (C7-CNG), ipsilateral phrenic nerve transfer with a vascularized ulnar nerve graft (P-VNG) and ipsilateral phrenic nerve transfer with conventional ulnar nerve grafting (P-CNG). Electrophysiological and histological examinations and functional evaluation were performed at different post-operative intervals. C7 root transfer was found to be superior to phrenic nerve transfer and VNG superior to CNG. Severance of the C7 nerve root was not found to affect limb function on the healthy side.

Summary. Background: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a tumor vascular disrupting agent under clinical trials as an adjacent antitumor agent. DMXAA is structurally similar to flavone-8-acetic acid (FAA), an old tumor vascular disrupting agent with antiplatelet and antithrombotic effects. In contrast to FAA, which causes bleeding in tumor patients, no bleeding has been reported in patients receiving DMXAA. Whether DMXAA also affects platelet function is not clear. Objectives: To determine the effects of DMXAA on platelet function and explore the underlying mechanisms. Methods and Results: DMXAA concentration-dependently inhibited human platelet aggregation and ATP release induced by U46619, arachidonic acid, ADP, collagen, or ristocetin. Furthermore, DMXAA inhibited phosphorylation of Erk1/2 and Akt downstream of thromboxane A 2 signaling inhibition. DMXAA also inhibited human platelet phosphodiesterase. The antiplatelet effects were further confirmed using mice administered DMXAA intravenously. DMXAA dramatically inhibited thrombus formation in FeCl 3 -injured mouse mesenteric arterial thrombus model and laser-injured mouse cremaster arteriole thrombus model. Notably, at a dose exhibiting antithrombotic effects similar to those of clopidogrel in mice, DMXAA did not significantly increase bleeding. Conclusions: For the first time, we found that tumor vascular disrupting agent DMXAA has potent antiplatelet and antithrombotic effects without any bleeding diathesis. As DMXAA inhibits platelet activity with safe profile, DMXAA could be used as an efficacious and safe antiplatelet drug.

Conclusions: Combination of SHR-1701 and famitinib showed promising activity with well-tolerated toxicities in pts with advanced PC or BTC. Updated results will be presented.Clinical trial identification: ChiCTR2000037927.