Jung Il Lee

INTRODUCTION: We conducted a phase 1 clinical trial in nine patients with mild-to-moderate Alzheimer's disease to evaluate the safety and dose-limiting toxicity of stereotactic brain injection of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). METHODS: cells/60 μL, respectively, into the bilateral hippocampi and right precuneus. RESULTS: No patient showed serious adverse events including fever during the 24-month follow-up period. During the 12-week follow-up period, the most common acute adverse event was wound pain from the surgical procedure (n = 9), followed by headache (n = 4), dizziness (n = 3), and postoperative delirium (n = 3). There was no dose-limiting toxicity. DISCUSSION: Administration of hUCB-MSCs into the hippocampus and precuneus by stereotactic injection was feasible, safe, and well tolerated. Further trials are warranted to test the efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov identifier NCT01297218 and NCT01696591.

BACKGROUNDS: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. OBJECTIVES: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). METHODS: cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. RESULTS: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. CONCLUSIONS: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.

Glioblastoma (GBM) is the most aggressive and most lethal brain tumor. As current standard therapy consisting of surgery and chemo-irradiation provides limited benefit for GBM patients, novel therapeutic options are urgently required. Forkhead box M1 (FoxM1) transcription factor is an oncogenic regulator that promotes the proliferation, survival, and treatment resistance of various human cancers. The roles of FoxM1 in GBM remain incompletely understood, due in part to pleotropic nature of the FoxM1 pathway. Here, we show the roles of FoxM1 in GBM stem cell maintenance and radioresistance. ShRNA-mediated FoxM1 inhibition significantly impeded clonogenic growth and survival of patient-derived primary GBM cells with marked downregulation of Sox2, a master regulator of stem cell phenotype. Ectopic expression of Sox2 partially rescued FoxM1 inhibition-mediated effects. Conversely, FoxM1 overexpression upregulated Sox2 expression and promoted clonogenic growth of GBM cells. These data, with a direct binding of FoxM1 in the Sox2 promoter region in GBM cells, suggest that FoxM1 regulates stemness of primary GBM cells via Sox2. We also found significant increases in FoxM1 and Sox2 expression in GBM cells after irradiation both in vitro and in vivo orthotopic tumor models. Notably, genetic or a small-molecule FoxM1 inhibitor-mediated FoxM1 targeting significantly sensitized GBM cells to irradiation, accompanying with Sox2 downregulation. Finally, FoxM1 inhibition combined with irradiation in a patient GBM-derived orthotopic model significantly impeded tumor growth and prolonged the survival of tumor bearing mice. Taken together, these results indicate that the FoxM1-Sox2 signaling axis promotes clonogenic growth and radiation resistance of GBM, and suggest that FoxM1 targeting combined with irradiation is a potentially effective therapeutic approach for GBM.

INTRODUCTION: The use of statins in nonalcoholic fatty liver disease (NAFLD) may reduce cardiovascular morbidity, although their effect on NAFLD itself is not well known. We aimed to investigate the role of statins on the development of de novo NAFLD and progression of significant liver fibrosis. METHODS: This study included 11,593,409 subjects from the National Health Information Database of the Republic of Korea entered in 2010 and followed up until 2016. NAFLD was diagnosed by calculating fatty liver index (FLI), and significant liver fibrosis was evaluated using the BARD score. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection. RESULTS: Among 5,339,901 subjects that had a FLI < 30 and included in the non-NAFLD cohort, 164,856 subjects eventually had NAFLD developed. The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65-0.67) and was independent of associated diabetes mellitus (DM) (with DM: AOR 0.44; 95% CI 0.41-0.46, without DM: AOR 0.71; 95% CI 0.69-0.72). From 712,262 subjects with a FLI > 60 and selected in the NAFLD cohort, 111,257 subjects showed a BARD score ≥ 2 and were defined as liver fibrosis cases. The use of statins reduced the risk of significant liver fibrosis (AOR 0.43; 95% CI 0.42-0.44), independent of DM (with DM: AOR 0.31; 95% CI 0.31-0.32, without DM: AOR 0.52; 95% CI 0.51-0.52). DISCUSSION: In this large population-based study, statin use decreased the risk of NAFLD occurrence and the risk of liver fibrosis once NAFLD developed.