Sulforaphane Increases Cyclin-Dependent Kinase Inhibitor, p21 Protein in Human Oral Carcinoma Cells and Nude Mouse Animal Model to Induce G2/M Cell Cycle Arrest

Previously, our group reported that sulforaphane (SFN), a naturally occurring chemopreventive agent from cruciferous vegetables, effectively inhibits the proliferation of KB and YD-10B human oral squamous carcinoma cells by causing apoptosis. In this study, treatment of 20 and 40 µM of SFN for 12 h caused a cell cycle arrest in the G2/M phase. Cell cycle arrest induced by SFN was associated with a significant increase in the p21 protein level and a decrease in cyclin B expression, but there was no change in the cyclin A protein level. In addition, SFN increased the p21 promoter activity significantly. Furthermore, SFN induced p21 protein expression in a nude mouse xenograft model suggesting that SFN is a potent inducer of the p21 protein in human oral squamous carcinoma cells. These findings show that SFN is a promising candidate for molecular-targeting chemotherapy against human oral squamous cell carcinoma

Supratentorial Gangliocytoma Mimicking Extra-axial Tumor: A Report of Two Cases

We report two cases of supratentorial gangliocytomas mimicking an extra-axial tumor. MR imaging indicated that the tumors were extra-axial, and meningiomas were thus initially diagnosed. Relative to gray matter, the tumors were hypointense on T1-weighted images and hyperintense on T2-weighted images. On contrast-enhanced T1-weighted images, homogeneous enhancement was observed, while CT scanning revealed calcification in one of the two cases

Molecular mechanism underlying the apoptotic modulation by ethanol extract of Pseudolarix kaempferi in mucoepidermoid carcinoma of the salivary glands

Background Pseudolarix kaempferi is a traditional Chinese natural product that possesses the potential cytotoxic effects against cancer. However, the precise molecular mechanism underlying its cytotoxic effects has not yet been completely elucidated. Here, we clarify the mechanism via which the ethanol extract of P. kaempferi (EEPK) leads to cytotoxicity mediated by apoptosis in mucoepidermoid carcinoma (MEC) originating from the salivary glands. Methods We investigated the mechanism underlying the anticancer efficacy of EEPK in human MEC in vitro by assessing mitochondrial dysfunction, mRNA levels, and morphological changes in apoptotic cell nuclei as well as by using a cytotoxicity assay, flow cytometric analysis, and western blotting. Results EEPK inhibited the growth of two human MEC cells and stimulated the induction of caspase-mediated apoptosis that was accompanied by mitochondrial membrane depolarization. Compared with the vehicle control groups, EEPK decreased myeloid cell leukemia-1 (Mcl-1) expression in both cells whereas it significantly decreased B cell lymphoma-2 (Bcl-2) expression in MC3 cells only. The EEPK-induced altered Mcl-1 expression was caused by translational inhibition and proteasomal degradation. Additionally, EEPK significantly increased p-Bcl-2 (Ser70) expression regardless of its total forms by facilitating the activation of the c-Jun N-terminal kinase (JNK) signaling pathway, which exhibited cell context dependency. Nevertheless, JNK activation following EEPK treatment was, at least in part, required for the proapoptotic efficacy of EEPK in both cells. Conclusions This study revealed that EEPK-induced alterations of Mcl-1 inhibition and JNK/Bcl-2 phosphorylation cause apoptosis and provided basic preclinical data for future clinical trials regarding therapy for patients with MEC. Graphic abstrac

Effect of delayed hospitalization on 3-year clinical outcomes according to renal function in patients with non-ST-segment elevation myocardial infarction

Background: We evaluated the effect of delayed hospitalization (symptom-to-door time [STD] ≥ 24 h) on 3-year clinical outcomes according to renal function in patients with non-ST-segment elevation myocardial infarction (NSTEMI) undergoing new-generation drug-eluting stent (DES) implantation. Methods: A total of 4513 patients with NSTEMI were classified into chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2, n = 1118) and non-CKD (eGFR ≥ 60 mL/min/1.73 m2, n = 3395) groups. They were further sub-classified into groups with (STD ≥ 24 h) and without (STD < 24 h) delayed hospitalization. The primary outcome was the occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, recurrent myocardial infarction, any repeat coronary revascularization, and stroke. The secondary outcome was stent thrombosis (ST). Results: After multivariable-adjusted and propensity score analyses, the primary and secondary clinical outcomes were similar in patients with or without delayed hospitalization in both CKD and non-CKD groups. However, in both the STD < 24 h and STD ≥ 24 h groups, MACCE (p < 0.001 and p < 0.006, respectively) and mortality rates were significantly higher in the CKD group than in the non-CKD group. However, ST rates were similar between the CKD and non-CKD groups and between the STD < 24 h and STD ≥ 24 h groups. Conclusions: Chronic kidney disease appears to be a much more important determinant of MACCE and mortality rates than STD in patients with NSTEMI

Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma

Background Using a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma. Method Based on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data. Results In SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4. Conclusions The results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1420020), Mid-career Researcher Program through the National Research Foundation (NRF) grant funded by the Korea government (Ministry of Science and ICT, 2017R1A2B2008422), and NRF grants funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (2012R1A1A1042953 and 2015R1A4A1041219). The funding bodies had no role in the design of the study, collection, analysis, and interpretation of data nor in writing the manuscript

In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background The primary cause of treatment failure in medulloblastomas (MB) is the development of leptomeningeal dissemination (seeding). For translational research on MB seeding, one of the major challenges is the development of reliable experimental models that simulate the seeding and growth characteristics of MBs. To overcome this obstacle, we improved an experimental mouse model by intracisternal inoculation of human MB cells and monitoring with in vivo live images. Methods Human MB cells (UW426, D283 and MED8A) were transfected with a firefly luciferase gene and a Thy1.1 (CD90.1) marker linked with IRES under the control of the CMV promoter in a retroviral DNA backbone (effLuc). The MB-effLuc cells were injected into the cisterna magna using an intrathecal catheter, and bioluminescence images were captured. We performed histopathological analysis to confirm the extent of tumor seeding. Results The luciferase activity of MB-effLuc cells displayed a gradually increasing pattern, which correlated with a quantitative luminometric assay. Live imaging showed that the MB-effLuc cells were diffusely distributed in the cervical spinal cord and the lumbosacral area. All mice injected with UW426-effLuc, D283-effLuc and MED8A-effLuc died within 51 days. The median survival was 22, 41 and 12 days after injection of 1.2 × 106 UW426-effLuc, D283-effLuc and MED8A-effLuc cells, respectively. The histopathological studies revealed that the MB-effLuc cells spread extensively and diffusely along the leptomeninges of the brain and spinal cord, forming tumor cell-coated layers. The tumor cells in the subarachnoid space expressed a human nuclei marker and Ki-67. Compared with the intracerebellar injection method in which the subfrontal area and distal spinal cord were spared by tumor cell seeding in some mice, the intracisternal injection model more closely resembled the widespread leptomeningeal seeding observed in MB patients. Conclusion The results and described method are valuable resources for further translational research to overcome MB seeding

Risk Factors for Predicting Hypoxia in Adult Patients Undergoing Bronchoscopy under Sedation

Background: Flexible bronchoscopy is one of the essential procedures for the diagnosis and treatment of pulmonary diseases. The purpose of this study was to identify the risk factors associated with the occurrence of hypoxia in adults undergoing flexible bronchoscopy under sedation. Methods: We retrospectively analyzed 2,520 patients who underwent flexible bronchoscopy under sedation at our tertiary care university hospital in South Korea January 1, 2013-December 31, 2014. Hypoxia was defined as more than 5%-point reduction in the baseline percutaneous oxygen saturation (SpO(2)) or SpO(2) 1 minute during the procedure. Results: The mean age was 64.7 +/- 13.5, and 565 patients developed hypoxia during the procedure. The mean sedation duration and midazolam dose for sedation were 31.1 minutes and 3.9 mg, respectively. The bivariate analysis showed that older age, a low forced expiratory volume in one second (FEV1), use of endobronchial ultrasound, the duration of sedation, and the midazolam dose were associated with the occurrence of hypoxia during the procedure, while the multivariate analysis found that age >60 (odds ratio [OR], 1.32), a low FEV1 (OR, 0.99), and a longer duration of sedation (>40 minutes; OR, 1.33) were significant risk factors. Conclusion: The findings suggest that patients older than age 60 and those with a low FEV1 tend to develop hypoxia during the bronchoscopy under sedation. Also, longer duration of sedation (>40 minutes) was a significant risk factor for hypoxia.11Nscopuskc