Inhibition of MUC1-C Increases ROS and Cell Death in Mouse Embryonic Stem Cells

Background and Objectives@#Embryonic stem (ES) cells have the capacity to self-renew and generate all types of cells.MUC1-C, a cytoplasmic subunit of MUC1, is overexpressed in various carcinomas and mediates signaling pathways to regulate intracellular metabolic processes and gene expression involved in the maintenance of cancer cells. However, the functional role of MUC1-C in ES cells is not well understood. In this study, we investigated the role of MUC1-C on growth, survival,: and differentiation of mouse ES (mES) cells. @*Methods@#and Results: Undifferentiated mES cells expressed the MUC1-C protein and the expression level was decreased during differentiation. Inhibition of MUC1-C, by the specific inhibitor GO201, reduced proliferation of mES cells.However, there was no prominent effect on pluripotent markers such as Oct4 expression and STAT3 signaling, and MUC1-C inhibition did not induce differentiation. Inhibition of MUC1-C increased the G1 phase population, decreased the S phase population, and increased cell death. Furthermore, inhibition of MUC1-C induced disruption of the ROS balance in mES cells. @*Conclusions@#These results suggest that MUC1-C is involved in the growth and survival of mES cells.

Inhibition of MUC1-C Increases ROS and Cell Death in Mouse Embryonic Stem Cells

Background and Objectives@#Embryonic stem (ES) cells have the capacity to self-renew and generate all types of cells.MUC1-C, a cytoplasmic subunit of MUC1, is overexpressed in various carcinomas and mediates signaling pathways to regulate intracellular metabolic processes and gene expression involved in the maintenance of cancer cells. However, the functional role of MUC1-C in ES cells is not well understood. In this study, we investigated the role of MUC1-C on growth, survival,: and differentiation of mouse ES (mES) cells. @*Methods@#and Results: Undifferentiated mES cells expressed the MUC1-C protein and the expression level was decreased during differentiation. Inhibition of MUC1-C, by the specific inhibitor GO201, reduced proliferation of mES cells.However, there was no prominent effect on pluripotent markers such as Oct4 expression and STAT3 signaling, and MUC1-C inhibition did not induce differentiation. Inhibition of MUC1-C increased the G1 phase population, decreased the S phase population, and increased cell death. Furthermore, inhibition of MUC1-C induced disruption of the ROS balance in mES cells. @*Conclusions@#These results suggest that MUC1-C is involved in the growth and survival of mES cells.

Splitomicin, a SIRT1 Inhibitor, Enhances Hematopoietic Differentiation of Mouse Embryonic Stem Cells

BACKGROUND AND OBJECTIVES: Embryonic stem (ES) cells have pluripotent ability to differentiate into multiple tissue lineages. SIRT1 is a class III histone deacetylase which modulates chromatin remodeling, gene silencing, cell survival, metabolism, and development. In this study, we examined the effects of SIRT1 inhibitors on the hematopoietic differentiation of mouse ES cells. METHODS AND RESULTS: Treatment with the SIRT1 inhibitors, nicotinamide and splitomicin, during the hematopoietic differentiation of ES cells enhanced the production of hematopoietic progenitors and slightly up-regulated erythroid and myeloid specific gene expression. Furthermore, treatment with splitomicin increased the percentage of erythroid and myeloid lineage cells. CONCLUSIONS: Application of the SIRT1 inhibitor splitomicin during ES cell differentiation to hematopoietic cells enhanced the yield of specific hematopoietic lineage cells from ES cells. This result suggests that SIRT1 is involved in the regulation of hematopoietic differentiation of specific lineages and that the modulation of the SIRT1 activity can be a strategy to enhance the efficiency of hematopoietic differentiation.

Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

Influence of Fish Oil-Containing Lipid Emulsions on Parenteral Nutrition-Associated Liver Disease in Neonates

PURPOSE: This study is a comparative evaluation of the incidence of parenteral nutrition-associated liver disease (PNALD) when administering intravenous fat emulsions containing fish oil. METHODS: The medical records of patients who were in the neonatal intensive care unit at Severance Hospital from January, 2012 to December 2015, were reviewed retrospectively. Patients who were administered either soybean oil (SO) or SMOF (containing soybean oil, medium chain triglycerides, olive oil, and fish oil) more than 14 days were included. The patients were excluded if they were administered both agents or had underlying hepatic disease. An increase in bilirubin to 2 mg/dL was defined as PNALD. RESULTS: PNALD occurred in only 8 out of a total of 77 patients: 6 out of 31 (19.4%) in the SO group and 2 out of 46 (4.3%) in the SMOF group (P=0.055). The number of patients, whose lab values, such as direct bilirubin, total bilirubin, asparate aminotransferase (AST), alanine amino-transferase, gamma-glutamyl transpeptidase, C-reactive protein, serum triglyceride, and alkaline phosphate, exceeded the normal range, were similar in both groups. The gestational age, birth body weight, and APGAR score at 1 min and 5 min were significantly higher in the SO group and the PN duration was significantly long in the SMOF group. Considering only term infants, there were no significant differences in baseline characteristics and incidence of PNALD. The number of patients whose AST exceeded the normal range was significantly higher in the SO group (P=0.034). CONCLUSION: The incidence of PNALD was similar in both groups. On the other hand, considering the tendency, there was a high correlation between the type of lipid emulsion and an increased direct bilirubin level in the SO group.

Diffuse alveolar hemorrhage and recombinant factor VIIa treatment in pediatric patients / 소아과

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders. The current treatment options, which include corticosteroids, transfusions, extracorporeal membrane oxygenation (ECMO), and immunosuppressants, have been limited and largely unsuccessful. Recombinant activated factor VII (rFVIIa) has been successfully administered, either systemically or bronchoscopically, to adults for the treatment of DAH, but there are few data on its use in pediatric patients. The current literature in the PubMed database was reviewed to evaluate the efficacy and risk of rFVIIa treatment for DAH in pediatric patients. This review discusses the diagnosis and treatment of DAH, as well as a new treatment paradigm that includes rFVIIa. Additionally, the risks and benefits of off-label use of rFVIIa in pediatric patients are discussed.

Diffuse alveolar hemorrhage and recombinant factor VIIa treatment in pediatric patients / 소아과

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders. The current treatment options, which include corticosteroids, transfusions, extracorporeal membrane oxygenation (ECMO), and immunosuppressants, have been limited and largely unsuccessful. Recombinant activated factor VII (rFVIIa) has been successfully administered, either systemically or bronchoscopically, to adults for the treatment of DAH, but there are few data on its use in pediatric patients. The current literature in the PubMed database was reviewed to evaluate the efficacy and risk of rFVIIa treatment for DAH in pediatric patients. This review discusses the diagnosis and treatment of DAH, as well as a new treatment paradigm that includes rFVIIa. Additionally, the risks and benefits of off-label use of rFVIIa in pediatric patients are discussed.

Toxic megacolon and interstitial pneumonia caused by cytomegalovirus infection in a pediatric patient with acute lymphoblastic leukemia receiving chemotherapy

No abstract available.

Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma

BACKGROUND: Methotrexate (MTX), one of the main drugs used to treat osteosarcoma, is a representative folic acid antagonist. Polymorphisms of various enzymes involved in the metabolism of MTX could contribute to differences in response to MTX in pediatric osteosarcoma patients. METHODS: Blood and tissue samples were obtained from 37 pediatric osteosarcoma patients who were treated with high-dose MTX therapy. The following 4 single nucleotide polymorphisms (SNPs) were analyzed: ATIC 347C>G, MTHFR 677C>T, MTHFR 1298A>C and SLC19A1 80G>A. Serial plasma MTX concentrations after high-dose MTX therapy and MTX-induced toxicities were evaluated. Correlations among polymorphisms, MTX concentrations and treatment-induced toxicities were assessed. RESULTS: Plasma MTX levels at 48 hours after high-dose MTX infusion were significantly associated with SLC19A1 80G>A (P=0.031). Higher plasma levels of MTX at 48 and 72 hours were significantly associated with MTX-induced mucositis (P=0.007 and P=0.046) and renal toxicity (P=0.002), respectively. SNP of SLC19A1 gene was associated with development of severe mucositis (P=0.026). CONCLUSION: This study suggests that plasma levels of MTX are associated with GI and renal toxicities after high-dose MTX therapy, and genetic polymorphisms that affect the metabolism of MTX may influence drug concentrations and development of significant side effects in pediatric patients treated with high-dose MTX.

Primary malignant rhabdoid tumor of greater omentum in 10-year-old girl

Contrary to metastatic tumors of the omentum, primary tumors of the omentum are very rare. A 10-year-old girl presented with low abdominal pain. Imaging studies showed a multiseptated hemorrhagic tumor. The mass from the omentum was removed completely and confirmed as a malignant rhabdoid tumor. Despite aggressive chemotherapy, she died after 9 months due to disease progression. We report one case of primary malignant rhabdoid tumor of the omentum for the first time.

6-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

Hepatic sinusoidal obstruction syndrome (hSOS) can be developed as a common complication after hematopoietic stem cell transplantation (HSCT), and rarely after 6-thioguanine-based chemotherapy without HSCT. A four-year-old boy with heterozygotic polymorphism for thiopurine methyltransferase (TPMT) developed hSOS after he received chemotherapy with cytarabine, cyclophosphamide, intrathecal methotrexate and 6-thioguanine (6-TG) as reconsolidation chemotherapy of acute lymphoblastic leukemia (ALL). He was treated with defibrotide, N-acetylcysteine, urusodeoxycholic acid, glutathione, and supportive care. He recovered completely in nine days without long-term complication, and completed chemotherapy with 6-mercaptopurine without severe complication. We report a case of hSOS developed in an ALL patient with TPMT heterozygote after 6-TG based reconsolidation chemotherapy.

6-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

Hepatic sinusoidal obstruction syndrome (hSOS) can be developed as a common complication after hematopoietic stem cell transplantation (HSCT), and rarely after 6-thioguanine-based chemotherapy without HSCT. A four-year-old boy with heterozygotic polymorphism for thiopurine methyltransferase (TPMT) developed hSOS after he received chemotherapy with cytarabine, cyclophosphamide, intrathecal methotrexate and 6-thioguanine (6-TG) as reconsolidation chemotherapy of acute lymphoblastic leukemia (ALL). He was treated with defibrotide, N-acetylcysteine, urusodeoxycholic acid, glutathione, and supportive care. He recovered completely in nine days without long-term complication, and completed chemotherapy with 6-mercaptopurine without severe complication. We report a case of hSOS developed in an ALL patient with TPMT heterozygote after 6-TG based reconsolidation chemotherapy.

A Case of an Imported Dengue Hemorrhagic Fever with Spontaneous Bleeding: Case Report and Review of the Literature / 소아감염

Dengue is an acute febrile viral disease which is found in tropical and sub-tropical regions around the world. Dengue fever has steadily increased in both incidence and distribution over the past 50 years. Even though Korea is not an endemic country for dengue fever, with the increasing numbers of overseas travelers in Korea, the numbers of imported dengue cases are steadily increasing. Here, we report a case of imported dengue hemorrhagic fever in a Korean child presenting with fever and epistaxis. Dengue fever should be considered if a patient who has a recent travel history to endemic areas showed classical symptoms.

Three-way Translocation of MLL/MLLT3, t(1;9;11)(p34.2;p22;q23), in a Pediatric Case of Acute Myeloid Leukemia / 대한진단검사의학회지

The chromosome band 11q23 is a common target region of chromosomal translocation in different types of leukemia, including infantile leukemia and therapy-related leukemia. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partners. We report a case of AML with a rare 3-way translocation involving chromosomes 1, 9, and 11: t(1;9;11)(p34.2;p22;q23). A 3-yr-old Korean girl presented with a 5-day history of fever. A diagnosis of AML was made on the basis of the morphological evaluation and immunophenotyping of bone marrow specimens. Flow cytometric immunophenotyping showed blasts positive for myeloid lineage markers and aberrant CD19 expression. Karyotypic analysis showed 46,XX,t(1;9;11)(p34.2;p22;q23) in 19 of the 20 cells analyzed. This abnormality was involved in MLL/MLLT3 rearrangement, which was confirmed by qualitative multiplex reverse transcription-PCR and interphase FISH. She achieved morphological and cytogenetic remission after 1 month of chemotherapy and remained event-free for 6 months. Four cases of t(1;9;11)(v;p22;q23) have been reported previously in a series that included cases with other 11q23 abnormalities, making it difficult to determine the distinctive clinical features associated with this abnormality. To our knowledge, this is the first description of t(1;9;11) with clinical and laboratory data, including the data for the involved genes, MLL/MLLT3.

Normalization of Red Cell Enolase Level Following Allogeneic Bone Marrow Transplantation in a Child with Diamond-Blackfan Anemia

We describe a girl with Diamond-Blackfan anemia with accompanying red cell enolase deficiency. At the age of 9 yr old, the patient received allogeneic bone marrow transplantation from her HLA-identical sister who had normal red cell enolase activity. While the post transplant DNA analysis with short tandem repeat has continuously demonstrated a stable mixed chimerism on follow-up, the patient remains transfusion independent and continues to show a steady increase in red cell enolase activity for over two and a half years following bone marrow transplantation.

Improved outcome in childhood ALL with intensive consolidation and hematopoietic stem cell transplant

BACKGROUND: Despite advances in chemotherapy, the prognosis of relapsed acute lymphoblastic leukemia (ALL) remains poor. Few studies on relapsed ALL have reported the importance of intensive consolidation followed with or without allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We evaluated the post-relapse outcomes in 47 Korean children with a first marrow relapse, and analyzed the prognostic factors. RESULTS: A second complete remission (CR) was achieved in 40 patients (85.1%), and at the time of this study, second CR was maintained in 12 of these patients. The estimated 3-yr event-free survival (EFS) rate after the first marrow relapse was 29.8+/-6.7%, and the overall survival (OS) rate was 45.3+/-7.5%. We found that second remission, consolidation of pediatric oncology group chemotherapy regimen (POG 9411), and HSCT significantly affected the outcome of the disease after relapse (P<0.001; P=0.004; P=0.05). CONCLUSION: The results of our study revealed that an intensified POG 9411 consolidation chemotherapy regimen followed by HSCT can improve the outcome of patients with relapsed ALL.

Effect of Modafinil and Methylphenidate on Sleep-Wake Architecture and EEG Power Spectra in Rats / 대한정신약물학회지

OBJECTIVE : Modafinil, methylphenidate, and caffeine are wakefulness-promoting substances. Previously, it was reported that caffeine-induced wakefulness differs from natural wakefulness in terms of the EEG spectral profiles. In order to evaluate whether wakefulness induced by other psychostimulants differs from both caffeine-induced and natural wakefulness, we examined the effects of the psychostimulants on sleep-wake architecture and EEG spectral profiles. METHODS : Eighteen Sprague-Dawley male rats underwent an EEG/EMG recording session from 10 : 30 to 17 : 30. They received caffeine (7.5, 15, 30 mg/kg i.p.), methylphenidate (1, 2, 5, 10 mg/kg i.p.) or modafinil (5, 10, 25, 50, 100 mg/kg i.p.) at 13 : 30. The number, total duration, and average duration of sleepwake states were obtained. EEG band powers were calculated by spectral analysis. Frequency bands were divided into the following ranges : D1, 1-2.5 Hz ; D2, 2.5-4.5 Hz ; T1, 4.5-7 Hz ; T2, 7-10 Hz ; SI, 10-14 Hz ; B1, 14-22 Hz ; B2, 22-34 Hz ; GA, 34-50 Hz. RESULTS : All three psychostimulants significantly and dose-dependently increased active wake duration and decreased slow-wave sleep. Equipotent doses of caffeine, methylphenidate, and modafinil for increasing active wake and decreasing slow-wave sleep were 7.5 mg/kg, 10 mg/kg, and 100 mg/kg, respectively. In equipotent doses, an increase of active wake duration by caffeine and methylphenidate was attributed to increases of both frequency and average duration of active wake state, whereas increase of active wake duration by modafinil was attributed to increase of average duration of active wake state only. In equipotent doses, caffeine and methylphenidate decreased the power of lower frequency bands (1-22 Hz), whereas modafinil did not. During slow-wave sleep, modafinil and methylphenidate increased the power of lower frequency bands, but caffeine did not. All the psychostimulants increased the power of the GA band, which was more prominent in the frontal cortex than the parietal cortex. CONCLUSION : These results suggest that moda-nil-induced wakefulness differs from caffeine- or methylphenidate-induced wakefulness in terms of EEG spectral profiles and sleep-wake architecture.

Initial Response to Treatment was Highly Associated with the Prognosis of Childhood Rhabdomyosarcoma: A Retrospective Analysis of a Single Center Experience in Korea / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Following the introduction of a multimodal approach to diagnosis and treatment, the prognosis of rhabdomyosarcoma (RMS) has markedly improved over the last three decades. However, there are few data on treatment outcomes in Korean patients. MATERIALS AND METHODS: We performed a retrospective analysis of 77 patients with RMS diagnosed and treated at Seoul National University Children's Hospital between 1986 and 2005. RESULTS: The overall 5-year survival and event-free survival rates for all patients were 77% and 59%, respectively. The Intergroup Rhabdomyosarcoma Study clinical grouping and initial response to treatment (20-week response) were important prognostic factors. CONCLUSIONS: The outcome of childhood RMS was closely associated with the initial staging and the initial response to treatment. Modulating therapies according to initial responses and risk factors is critical, and new treatment strategies for high-risk patients are needed.

Trend of Tuberculous Meningitis since 1970

PURPOSE: The incidence of tuberculous meningitis has reportedly decreased from 4.2% in 1970 to 1.8% in 1990 in Korea; however, tuberculous meningitis, which spreads hematogenously, claiming majority of mortality in childhood tuberculosis, still poses serious problems. This study was performed to evaluate the recent trend of tuberculous meningitis. METHODS: We compared with three groups of tuberculous meningitis, two were our previous reports on tuberculous meningitis, 106 cases1) from 1971 to 1979 were assigned as group I, 60 cases2) from 1982 to 1988 as group II and we reviewed medical record of 16 cases from 1989 to 1994 as group III. RESULTS: 1) The incidence of tuberculous meningitis among the total admitted patients in groups I, II, and III were 0.92, 0.27, and 0.06%, decreasing with a slope of -0.063% per year, and a correlation coefficient of -0.892. 2) The age proportion among children under age 1 year were 17.9, 8.3, and 6.3%, espectively for three groups and those over age 9-10 years were 11.3, 13.4, and 43.8%, indicating that proportion of under age 1 year declined, whereas it increased in older aged children. 3) The overall male to female ratio was 1.43 : 1, and peak seasonal incidence was not noted. 4) There was no differences in tuberculous family history with 41.5% in group I, and 43.8% in group III; BCG vaccination rate was increased significantly from 16.0% in group I up to 68.6% in group III(p<0.001); and the positive tuberculin skin test reactivity significantly increased from 29.6% in group I to 68.8% in group III(p<0.01). 5) On chest X-ray, the rate of finding tuberculous lesion did not significantly change among 3 groups with 69.8, 58.3, and 87.5%, while the rate of associated miliary tuberculosis was significantly reduced with 36.8, 28.3, and 0%(p<0.05). 6) The cure rate was 65.1, 68.4, and 87.5%, respectively and the cure rate of clinical stage 3 improved from 36.1% in group I to 66.7% in group III, but they showed no significant difference between groups(p<0.05). The mortality rate was 5.7, 14.9, and 12.5%, respectively and there was no significant difference between groups(p<0.05). 7) Hospital days under 14 days were 67.9, 23.3, and 6.3%, respectively; those over 21 days were 3.8, 45.0, and 68.8%, respectively, indicating the hospital days became prolonged(p<0.001). 8) Brain CT was performed in group III(13/16), with abnormal findings found in 84.6%. The abnormal findings were hydrocephalus in 5 cases(26.3%, ventriculoperitoneal shunt was done in 3 cases); and basal cisternal enhancement, and infarction 3 cases each. Complication rate was not improved with 35.0% in group I and 31.2% in group III. CONCLUSIONS: During 25 years, the incidence of tuberculous meningitis significantly decreased with the increased BCG vaccination rate; and the age of the affected children tended to increase. It is noted, however, that the mortality rate and neurologic complication of the affected children were not substantially improved, stressing early diagnosis and vigorous treatment on tuberculosis in children.