Immune checkpoint inhibitors may be associated with various adverse events, including encephalitis. Here, we report a case of encephalopathy associated with pembrolizumab therapy. A 60-year-old male diagnosed with cholangiocarcinoma with peritoneal seeding presented altered mentality and cognitive function after using pembrolizumab. Electroencephalogram showed mild diffuse cerebral dysfunction. Cerebrospinal fluid (CSF) study showed no evidence of infection or autoimmune disease and no paraneoplastic antibody was detected from CSF and serum. After high-dose methylprednisolone intravenous infusion, patient’s mentality was fully recovered.

Gene transfer of basic fibroblast growth factor (bFGF) has been shown to induce significant endothelial migration and angiogenesis in ischemic disease models. Here, we investigate what factors are secreted from skeletal muscle cells (SkMCs) transfected with bFGF gene and whether they participate in endothelial cell migration. We constructed replication-defective adenovirus vectors containing the human bFGF gene (Ad/bFGF) or a control LacZ gene (Ad/LacZ) and obtained conditioned media, bFGF-CM and LacZ-CM, from SkMCs infected by Ad/bFGF or Ad/LacZ, respectively. Cell migration significantly increased in HUVECs incubated with bFGF-CM compared to cells incubated with LacZ-CM. Interestingly, HUVEC migration in response to bFGF-CM was only partially blocked by the addition of bFGF-neutralizing antibody, suggesting that bFGF-CM contains other factors that stimulate endothelial cell migration. Several proteins, matrix metalloproteinase-1 (MMP-1), plasminogen activator inhibitor-1 (PAI-1), and cathepsin L, increased in bFGF-CM compared to LacZ-CM; based on 1-dimensional gel electrophoresis and mass spectrometry. Their increased mRNA and protein levels were confirmed by RT-PCR and immunoblot analysis. The recombinant human bFGF protein induced MMP-1, PAI-1, and cathepsin L expression in SkMCs. Endothelial cell migration was reduced in groups treated with bFGF-CM containing neutralizing antibodies against MMP-1 or PAI-1. In particular, HUVECs treated with bFGF-CM containing cell-impermeable cathepsin L inhibitor showed the most significant decrease in cell migration. Cathepsin L protein directly promotes endothelial cell migration through the JNK pathway. These results indicate that cathepsin L released from SkMCs transfected with the bFGF gene can promote endothelial cell migration.
Antibodies, Neutralizing/immunology ; Cathepsin L/genetics/*metabolism ; *Cell Movement ; Cells, Cultured ; Comet Assay ; Dependovirus/genetics ; Endothelial Cells/cytology/*metabolism ; Fibroblast Growth Factor 2/genetics/immunology/*metabolism ; Gene Transfer Techniques ; Humans ; Immunoblotting ; JNK Mitogen-Activated Protein Kinases ; Lac Operon/genetics ; Mass Spectrometry ; Matrix Metalloproteinase 1/biosynthesis/genetics ; Muscle, Skeletal/*metabolism ; Neovascularization, Physiologic ; Plasminogen Activator Inhibitor 1/biosynthesis/genetics ; RNA, Messenger/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction

BACKGROUND AND OBJECTIVES: Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model. MATERIALS AND METHODS: We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIV-TAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin (1 microM) was added for 1 hour prior to doxorubicin (1 microM) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins. RESULTS: The survivin level was significantly reduced in a dose dependent manner up to 1 microM of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury. CONCLUSION: Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.
Apoptosis ; Caspase 3 ; Cell Death ; Cell Survival ; Cyclic AMP Response Element-Binding Protein ; Doxorubicin ; Humans ; Inhibitor of Apoptosis Proteins ; Mitochondria ; Myocytes, Cardiac ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Phosphotransferases ; Transcription Factors

OBJECTIVE: This study was conducted to investigate satisfaction surveys of the emergency medical system in Korea administered to both members of the Korean Society of Emergency Medicine and patients and their guardians. METHODS: The joint survey was conducted by the Korea Scientist Journalists Association and the Public Affairs Committee of the Korean Society of Emergency Medicine. Questionnaires administered to each group included questions about the general environment, safety, and overcrowding. Satisfaction of medical staffs and awareness of cardiopulmonary resuscitation were only included in the patient questionnaire, while public health was only surveyed in the member questionnaire. The satisfaction was evaluated on a 5-point scale. RESULTS: Patient questionnaires were answered by 20 of 413 national emergency medical centers, and about 4.3% of the medical institutions participated in the questionnaire. A total of 704 reply sheets were returned by patients. Member questionnaires were answered by 280 of the 1,108 members (25%). Among patients, the lowest satisfaction was the item of “medical expenses,” followed by “waiting time”. Among providers, the lowest satisfaction was “appropriateness of medical staff”, while the highest complaint was “overcrowding.” CONCLUSION: Emergency care users had the lowest satisfaction with “medical expenses,” while members had the lowest satisfaction with “lack of manpower” and were most dissatisfied with “violence” and “overcrowding.”
Cardiopulmonary Resuscitation ; Emergencies* ; Emergency Medical Services ; Emergency Medicine* ; Health Care Surveys ; Humans ; Job Satisfaction ; Joints* ; Korea* ; Medical Staff ; Patient Satisfaction ; Public Health