Recombinant Thrombomodulin Has an Antitumor Effect and Enhances the Sensitivity of Gemcitabine Treatment of Pancreatic Cancer via G-protein Coupled Receptor 15

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Spontaneous Pathological Complete Regression of Hepatocellular Carcinoma

Several possible mechanisms for spontaneous regression of hepatocellular carcinoma (HCC) have been reported. Spontaneous complete regression of HCC is extremely rare. We herein report a case of spontaneous pathological complete regression of HCC following decrement of elevated serum alpha-fetoprotein (AFP). The serum AFP of a 74-year-old man who underwent hepatic resection for HCC twice increased up to 7,529 ng/mL and then spontaneously decreased to 404 ng/mL in 2 months. Computed tomography, magnetic resonance imaging, and angiography revealed a liver tumor in segment 7 without early enhancement. With a diagnosis of recurrent HCC, partial hepatic resection was performed. The resected specimens revealed no HCC macroscopically, and pathological examination revealed only a small area with cell dysplasia. The patient remains well with normal serum AFP and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels for 29 months after the third hepatic resection without recurrence of HCC. We describe a case of spontaneous pathological complete regression of HCC following decrement of elevated serum AFP. Further studies are needed to identify the mechanism(s) of spontaneous regression of HCC

Nardilysin-Regulated Scission Mechanism Activates Polo-Like Kinase 3 To Suppress the Development of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism

Tetrahydrouridine Inhibits Cell Proliferation through Cell Cycle Regulation Regardless of Cytidine Deaminase Expression Levels

Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance. Therefore, a combination therapy of THU and gemcitabine is considered to be a potential and promising treatment for tumors with highly expressed CDA. In this study, we found that THU has an alternative mechanism for inhibiting cell growth which is independent of CDA expression. Three different carcinoma cell lines (MIAPaCa-2, H441, and H1299) exhibited decreased cell proliferation after sole administration of THU, while being unaffected by knocking down CDA. To investigate the mechanism of THU-induced cell growth inhibition, cell cycle analysis using flow cytometry was performed. This analysis revealed that THU caused an increased rate of G1-phase occurrence while S-phase occurrence was diminished. Similarly, Ki-67 staining further supported that THU reduces cell proliferation. We also found that THU regulates cell cycle progression at the G1/S checkpoint by suppressing E2F1. As a result, a combination regimen of THU and gemcitabine might be a more effective therapy than previously believed for pancreatic carcinoma since THU works as a CDA inhibitor, as well as an inhibitor of cell growth in some types of pancreatic carcinoma cells

Renal Infarction during Anticoagulant Therapy after Living Donor Liver Transplantation

Introduction: Liver transplant recipients are at risk for complications of vascular thrombosis. The reconstructed hepatic artery and portal vein thrombosis potentially result in hepatic failure and graft loss. Renal infarction is a rare clinical condition, but in severe cases, it may lead to renal failure. We herein report a case of renal infarction after living donor liver transplantation (LDLT) during anticoagulant therapy. Case Presentation: A 60-year-old woman with end-stage liver disease due to primary biliary cholangitis underwent LDLT with splenectomy. Postoperatively, tacrolimus, mycophenolate mofetil, and steroid were used for initial immunosuppression therapy. On postoperative day (POD) 5, enhanced computed tomography (CT) revealed splenic vein thrombosis, and anticoagulant therapy with heparin followed by warfarin was given. Follow-up enhanced CT on POD 20 incidentally demonstrated right renal infarction. The patient’s renal function was unchanged and the arterial flow was good, and the splenic vein thrombosis resolved. At 4 months postoperatively, warfarin was discontinued, but she developed recurrent splenic vein thrombosis 11 months later, and warfarin was resumed. As of 40 months after transplantation, she discontinued warfarin and remains well without recurrence of splenic vein thrombosis or renal infarction. Conclusion: Renal infarction is a rare complication of LDLT. In this case, renal infarction was incidentally diagnosed during anticoagulant therapy and was successfully treated

Tetrahydrouridine Inhibits Cell Proliferation through Cell Cycle Regulation Regardless of Cytidine Deaminase Expression Levels

Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance. Therefore, a combination therapy of THU and gemcitabine is considered to be a potential and promising treatment for tumors with highly expressed CDA. In this study, we found that THU has an alternative mechanism for inhibiting cell growth which is independent of CDA expression. Three different carcinoma cell lines (MIAPaCa-2, H441, and H1299) exhibited decreased cell proliferation after sole administration of THU, while being unaffected by knocking down CDA. To investigate the mechanism of THU-induced cell growth inhibition, cell cycle analysis using flow cytometry was performed. This analysis revealed that THU caused an increased rate of G1-phase occurrence while S-phase occurrence was diminished. Similarly, Ki-67 staining further supported that THU reduces cell proliferation. We also found that THU regulates cell cycle progression at the G1/S checkpoint by suppressing E2F1. As a result, a combination regimen of THU and gemcitabine might be a more effective therapy than previously believed for pancreatic carcinoma since THU works as a CDA inhibitor, as well as an inhibitor of cell growth in some types of pancreatic carcinoma cells