We examined the p53 protein overexpression and evaluated its correlation with pathobiological variables, including: (1) patient age, sex, tumor size, histological type and grade, invasion depth, vascular invasion, perineural invasion and lymph node status; (2) the Ki-67 labeling index in 100 gastric carcinomas; and (3) the DNA ploidy pattern, S phase fraction (SPF), and the proliferation index (PI) in 84 cases using flow cytometry. The positive rate of p53 staining was 48% and the p53 immunoreactivity was independent of variable clinicopathologic factors. No correlation was made between the Ki-67 labeling index with p53 immunostaining and DNA ploidy parameters. Aneuploidy rate was slightly higher in the p53 positive group (55.6%) than the p53 negative group (44.4%)(p=0.097). The mean values of SPF and PI were significantly higher in the p53 protein positive group. Aneuploidy was more often observed in the intestinal type (p=0.038), advanced gastric carcinoma (p=0.015) and lymph node positive group(p=0.039). The above results suggest that although the p53 protein overexpression has no significant correlation with pathological factors and the Ki-67 labeling index, it may play an important role in tumor cell proliferation. Since p53 protein overexpression was slightly higher in the aneuploidy group showing significant correlation with poor prognostic parameters, it is thought that re-evaluation of the p53 mutation by molecular biological study is needed.
Aneuploidy ; Cell Proliferation ; DNA* ; Flow Cytometry ; Humans ; Lymph Nodes ; Ploidies* ; S Phase

p27(kip1) protein, a cyclin-dependent kinase inhibitor, has been reported to be a powerful negative prognostic marker in patients with breast carcinoma. However, to this day, studies on p27(kip1) protein expression in ductal carcinoma in situ (DCIS) have been extremely limited. We studied the immunohistochemical expression of p27(kip1) protein in 49 cases of the DCIS and compared the findings to the clinicopathologic parameters, cyclin D1, p53 and estrogen receptor (ER). Positive nuclear staining of p27(kip1) protein was identified in 23 (46.9%) cases. The p27(kip1) protein expression correlated positively with the cyclin D1 immunopositivity (p<0.005) and ER expression (p<0.005). No significant associations were seen in the p27(kip1) protein expression and clinicopathologic parameters. The overexpression of cyclin D1 (59.2% of the cases) correlated positively with ER expression (p<0.001). The p53 protein expression was identified in 30.6% and seemed to be correlated inversely with ER expression (p=0.06). The DCISs with high grade nuclei were more likely to be p53-positive (p<0.05). Our data suggest that the expression of p27(kip1) protein as well as cyclin D1 and p53 protein may be influenced by the ER status in DCIS. The significantly positive correlation of p27(kip1) protein and cyclin D1 expression (p<0.005) supports the theory that the balance of the two opposing signals is important in determining the cell proliferation in breast cancers. Therefore, a comprehensive understanding of loop reaction of p27(kip1)-cyclin D1-ER may be necessary for the treatment of DCIS.
Breast Neoplasms ; Breast* ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Cell Proliferation ; Cyclin D1* ; Cyclins* ; Estrogens ; Humans ; Phosphotransferases ; Staphylococcal Protein A

We previously demonstrated that 1-methyl-4-phenylpyridinium (MPP+) causes caspase-independent, non-apoptotic death of dopaminergic (DA) neuronal cells. Here, we specifically examined whether change of glucose concentration in culture medium may play a role for determining cell death modes of DA neurons following MPP+ treatment. By incubating MN9D cells in medium containing varying concentrations of glucose (5~35 mM), we found that cells underwent a distinct cell death as determined by morphological and biochemical criteria. At 5~10 mM glucose concentration (low glucose levels), MPP+ induced typical of the apoptotic dell death accompanied with caspase activation and DNA fragmentation as well as cell shrinkage. In contrast, MN9D cells cultivated in medium containing more than 17.5 mM (high glucose levels) did not demonstrate any of these changes. Subsequently, we observed that MPP+ at low glucose levels but not high glucose levels led to ROS generation and subsequent JNK activation. Therefore, MPP+-induced cell death only at low glucose levels was significantly ameliorated following co-treatment with ROS scavenger, caspase inhibitor or JNK inhibitor. We basically confirmed the quite similar pattern of cell death in primary cultures of DA neurons. Taken together, our results suggest that a biochemically distinct cell death mode is recruited by MPP+ depending on extracellular glucose levels.
1-Methyl-4-phenylpyridinium ; Cell Death* ; DNA Fragmentation ; Dopaminergic Neurons* ; Glucose* ; Neurons ; Parkinson Disease ; Reactive Oxygen Species

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Most cases are sporadic and its etiology is incompletely understood. However, increasing evidence suggests that oxidative stress and mitochondrial dysfunction may be involved in the pathogenesis of Parkinson's disease. The aim of this study was to investigate changes in mitochondrial protein profiles during dopaminergic neuronal cell death using two-dimensional gel electrophoresis in conjunction with mass spectrometry. Several protein spots were found to be significantly altered following treatment of MN9D dopaminergic neuronal cells with 6-hydroxydopamine (6-OHDA). Among several identified candidates, TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone, was released from the mitochondria into the cytosol in MN9D cells as well as primary cultures of dopaminergic neurons following 6-OHDA treatment. This event was drug-specific in that such apoptotic inducers as staurosporine and etoposide did not cause translocation of TRAP1 into the cytosol. To our knowledge, the present study is the first to demonstrate the drug-induced subcellular translocation of TRAP1 during neurodegeneration. Further studies delineating cellular mechanism associated with this phenomenon and its functional consequence may provide better understanding of dopaminergic neurodegeneration that underlies PD pathogenesis.
Cell Death ; Cytosol ; Dopaminergic Neurons ; Electrophoresis, Gel, Two-Dimensional ; Etoposide ; Mass Spectrometry ; Mitochondria* ; Mitochondrial Proteins ; Molecular Chaperones ; Necrosis* ; Neurodegenerative Diseases ; Oxidative Stress ; Oxidopamine* ; Parkinson Disease ; Proteomics ; Staurosporine ; Substantia Nigra ; TNF Receptor-Associated Factor 1

Background and Objectives: Cryoballoon catheter ablation for the treatment of patients with symptomatic atrial fibrillation (AF) has been adopted globally, but there are limited multicenter reports of 12-month outcomes in the Korean patient population. This analysis evaluated the clinical performance and safety of cryoballoon ablation (CBA) according to standard-of-care practices in Korea. Methods: This evaluation of Korean patients with AF was conducted within the larger Cryo Global Registry, which is a prospective, multicenter, post-market registry. Freedom from a ≥30-second recurrence of atrial arrhythmias (after a 90-day blanking period until 12 months) and procedural safety were examined in subjects treated with CBA at 3 Korean centers. Results: Overall, 299 patients with AF (60±11 years old, 24.7% female, 50.5% paroxysmal AF) underwent CBA using the Arctic Front Advance cryoballoon. Of those, 298 were followed-up for at least 12 months. Mean procedure-, left atrial dwell- and fluoroscopy time was 76±21 minutes, 56±23 minutes, and 27±23 minutes, respectively. Freedom from AF recurrence at 12 months was 83.9% (95% confidence interval [CI], 76.9–88.9%) in the paroxysmal and 61.6% (95% CI, 53.1–69.0%) in the persistent AF cohort. Rhythm monitoring was performed on average 4.7±1.4 times during the follow-up period. Serious device- or procedure-related adverse events occurred in 2 patients (0.7%). The 12-month Kaplan-Meier estimate of freedom from repeat ablation and cardiovascular-related hospitalization was 93.8% (95% CI, 90.4–96.1%) and 89.7% (95% CI, 85.6–92.7%), respectively. Conclusions CBA is an efficient, effective, and safe procedure for the treatment of AF patients when used according to real-world practices in Korea.Trial Registration: ClinicalTrials.gov Identifier: NCT02752737

The accuracy of fine needle aspiration cytology(FNAC) of the lymph node was investigated through a review of 176 FNAC cases and the corresponding biopsies. We chose 157 FNAC cases after the exclusion of 19 inadequate ones. Sensitivity of malignancy was 94.0%, specificity 100%, false negativity 6.0%, and false positivity 0.0%. The overall diagnostic accuracy was 96.8%. Sensitivity of metastatic carcinoma was 98.0% and that of malignant lymphoma was 87.9%. False negative cases included one metastatic carcinoma and four malignant lymphomas. The aspirates of metastatic carcinoma with false negativity exhibited a diffuse smear of keratin debris without viable cells, which led to the difficulty in differentiation from benign epithelial cyst. The cases of malignant lymphoma with false negative diagnosis were two Hodgkin diseases, one Lennert's lymphoma, and one peripheral T cell lymphoma in the histologic sections. On the analysis of 39 cases of tuberculosis, 17 cases(43.6%) were diagnosed as tuberculosis, 4(10.3%) as granulomatous lymphadenitis, 3(7.7%) as necrotizing lymphadenitis, and 15(38.5%) as reactive hyperplasia or pyogenic inflammation. Sensitivity of tuberculosis was 53.9%. In conclusion, lymph node FNAC is an excellent non-invasive diagnostic tool for the diagnosis of metastatic carcinoma. The diagnostic accuracy of malignant lymphoma could be improved with flow cytometry or polymerase chain reaction for antigen receptor genes. For the FNAC diagnosis of tuberculosis, AFB stain, culture, and PCR would be helpful as adjuvant techniques.
Biopsy* ; Biopsy, Fine-Needle* ; Diagnosis ; Flow Cytometry ; Hyperplasia ; Inflammation ; Lymph Nodes* ; Lymphadenitis ; Lymphoma ; Lymphoma, T-Cell, Peripheral ; Polymerase Chain Reaction ; Receptors, Antigen ; Sensitivity and Specificity ; Tuberculosis

There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.
Cell Death ; Drug Design ; Nervous System Diseases ; Neurodegenerative Diseases ; Neurons ; Parkinson Disease ; Regeneration ; Stem Cells ; Organelle Biogenesis

Calbindin-D28K has been implicated in the regulation of neuronal cell death. Previously, we demonstrated that calbindin-D28K prevents staurosporine (STS)-induced caspase activation and subsequent apoptosis in a neuronal cell line. However, the role of calbindin-D28K in STS-induced activation of calpain and necrotic cell death was not identified. Staurosporine induced the elevation of intracellular calcium after 1 hr of treatment. Overexpression of calbindin-D28K and presence of a calcium chelator, BAPTA, prevented the increase of calcium in STS-treated cells. Cleavage of Bax by calpain was prevented by the overexpressed calbindin-D28K. Permeabilization of the plasma membrane, a factor in necrosis, as well as apoptotic change of the nucleolus induced by STS, was prevented by calbindin-D28K. Thus, our study suggests that calbindin-D28K may exert its protective functions by preventing calpain activation in necrotic cell death, in addition to its effect on the caspase-apoptosis pathway.
Apoptosis ; Calbindin 1* ; Calcium ; Calpain ; Cell Death ; Cell Line ; Cell Membrane ; Membranes* ; Necrosis ; Neurons ; Staurosporine

Central diabetes insipidus (CDI) is a clinical syndrome that result from a failure of the neurohypophyseal axis to produce or release a sufficient quantity of arginine vasopressin (AVP) to permit normal function of the urinary concentrating mechanism. Polyuria and polydipsia are the symptoms associated with CDI. The most common cause of CDI is idiopathic variety and head trauma, neurohypophyseal surgery, primary or metastatic brain tumors acount for most of the remaining cases. CDI in Langerhans cell histiocytosis (LCH) is thought to be to infiltration of the hypothalamus-neurohypophyseal system. We report a patient with CDI and LCH underwent water depriviation test, MR imaging of the pituitary-hypothalamic region, and VATS associated open lung biopsy.
Arginine Vasopressin ; Axis, Cervical Vertebra ; Biopsy ; Brain Neoplasms ; Craniocerebral Trauma ; Diabetes Insipidus* ; Diabetes Insipidus, Neurogenic ; Histiocytosis* ; Histiocytosis, Langerhans-Cell ; Humans ; Lung ; Magnetic Resonance Imaging ; Polydipsia ; Polyuria ; Thoracic Surgery, Video-Assisted

OBJECTIVES: We examined whether pericardial adipose tissue (PAT) is predictive of prediabetes and type 2 diabetes over time. METHODS: In total, 2,570 adults without prediabetes/diabetes from the Coronary Artery Risk Development in Young Adults Study were followed up over 15 years. PAT volume was measured by computed tomography scans, and the new onset of prediabetes/diabetes was examined 5 years, 10 years, and 15 years after the PAT measurements. Multivariable Cox regression models were used to examine the association between the tertile of PAT and incident prediabetes/diabetes up to 15 years later. The predictive ability of PAT (vs. waist circumference [WC], body mass index [BMI], waist-to-height ratio [WHtR]) for prediabetes/diabetes was examined by comparing the area under the receiver operating characteristic curve (AUC). RESULTS: The highest tertile of PAT was associated with a 1.56 times (95% confidence interval [CI], 1.03 to 2.34) higher rate of diabetes than the lowest tertile; however, no association was found between the highest tertile of PAT and prediabetes in the fully adjusted models, including additional adjustment for BMI or WC. In the fully adjusted models, the AUCs of WC, BMI, WHtR, and PAT for predicting diabetes were not significantly different, whereas the AUC of WC for predicting prediabetes was higher than that of PAT. CONCLUSIONS PAT may be a significant predictor of hyperglycemia, but this association might depend on the effect of BMI or WC. Additional work is warranted to examine whether novel adiposity indicators can suggest advanced and optimal information to supplement the established diagnosis for prediabetes/diabetes.