ABSTRACT
SETTING: Tuberculosis (TB) and diabetes mellitus (DM) remain global health concerns. Metformin has recently received attention for its anti-tuberculosis effects.OBJECTIVE: To evaluate the risk of TB development in elderly DM patients treated with metformin compared with sulfonylureas.DESIGN: We performed a retrospective cohort study using the National Health Insurance Service-Senior database. The participants were type-2 DM (T2DM) patients aged ≥60 years between 1 January 2003 and 31 December 2013. We matched each metformin user to a sulfonylurea user using a propensity score. A Cox proportional hazards model was used to compare the risk of TB in metformin and sulfonylurea users.RESULTS: After propensity score matching, 12,582 patients were in each group. The TB incidence was 280.2/100 000 person-years (py) for metformin users and 394.5/100 000 py for sulfonylurea users. Metformin users had a lower risk of TB development than sulfonylurea users (adjusted hazard ratio 0.74, 95%CI 0.58-0.95), and the results were stronger for male participants. A dose-response relationship between metformin use and TB development was found in both sexes.CONCLUSION: Metformin use was associated with a decreased risk of TB development among elderly T2DM patients compared with sulfonylurea use.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Tuberculosis/epidemiology , Aged , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Hypoglycemic Agents/pharmacology , Incidence , Male , Metformin/pharmacology , Retrospective Studies , Sulfonylurea Compounds/administration & dosageABSTRACT
BACKGROUND: Patients with interstitial lung disease (ILD) constitute a substantial disease burden. Although ILD outcomes have been investigated, the risk of death due to ILD has not been studied in the light of confounders and comorbidities. In this nationwide, 11-year longitudinal, population-based study, we aimed to discover if ILD is an independent risk factor for mortality. DESIGN: Data on 1 031 392 (2.2%) randomly selected subjects from 47 279 373 Korean residents were collected from the 2002 Korean National Health Insurance database. The ILD group comprised patients with an initial diagnosis of ILD between January 2003 and December 2007. Each patient was followed until 2013. We used Cox proportional hazard regression analyses to calculate the risk of death adjusted for comorbidities and confounders. RESULTS: ILD developed in 783 of the 303 385 subjects during the 5-year period (51 per 100 000 person-years). Death occurred in 157 (23.2%) cases and 272 controls (10.4%). ILD was significantly associated with the risk of death (hazard ratio 2.1, 95% confidence interval [CI] 1.6-2.7) and for those aged 40-59, 60-69 and î¶70 years. A high proportion of patients with ILD died due to respiratory causes. CONCLUSION: ILD patients had a significantly higher risk of death than matched controls, after adjustment for potential confounders and comorbidities.
Subject(s)
Cost of Illness , Lung Diseases, Interstitial/mortality , Adult , Age Factors , Aged , Female , Humans , Longitudinal Studies , Lung Diseases, Interstitial/epidemiology , Male , Middle Aged , Proportional Hazards Models , Republic of Korea/epidemiology , Risk FactorsABSTRACT
AIM: In this study, the impact of serum bilirubin on new-onset type 2 diabetes mellitus (T2DM) in Korean adults was investigated. METHODS: Data were obtained from the Korean Genome and Epidemiology Study (KoGES), a population-based prospective cohort study. The study enrolled 8650 adults (4015 men and 4635 women), aged 40 to 69 years, who underwent a mean follow-up of 8.4 years. The study population was divided into quartiles (Q) of serum bilirubin levels, with cut-off points at 0.46, 0.61 and 0.82mg/dL for men, and 0.35, 0.47 and 0.61mg/dL for women. T2DM was defined based on the following data: fasting blood glucose≥7.0mmol/L, HbA1c level≥6.5% or 2-h plasma glucose≥11.1mmol/L during a 75-g oral glucose tolerance test. RESULTS: Over the mean 8.4-year follow-up, 786 participants (9.1%) developed T2DM. Compared with Q1, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM incidence were 0.52 (0.36-0.74) in men and 0.56 (0.38-0.83) in women aged ≥50 years, respectively, in the highest Q group after adjusting for possible confounding factors. These significant results persisted in those with impaired glucose tolerance and impaired fasting glucose. CONCLUSION: The results of this study reveal a protective role for serum total bilirubin on new-onset T2DM in Korean men and women. In addition, serum total bilirubin had favourable effects on new-onset T2DM in those with impaired glucose tolerance and impaired fasting glucose.
Subject(s)
Bilirubin/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Adult , Aged , Blood Glucose , Female , Humans , Male , Middle Aged , Prospective Studies , Republic of Korea/epidemiologyABSTRACT
BACKGROUND: Although a contributory role of vitamin D levels for the development of chronic hepatitis C has been suggested, the efficacy of vitamin D supplementation in combination with conventional antiviral therapy consisting of pegylated interferon-α (Peg-IFN-α) injection and oral ribavirin (RBV) remains unclear. We investigated its efficacy in the treatment of chronic hepatitis C via a meta-analysis of randomised controlled trials. METHODS: We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov and the bibliographies of relevant articles to locate additional publications in September 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. RESULTS: Of 522 articles meeting our initial criteria, a total of seven open-label, randomised controlled trials involving 548 participants, were included in the final analysis. Vitamin D supplementation in combination with Peg-IFN-α injection and oral RBV significantly increased the rate of viral response for hepatitis C at 24 weeks after treatment in a random-effects meta-analysis (relative risk = 1.30; 95% confidence interval = 1.04-1.62; I2 = 75.9%). Also, its significant efficacy was observed in patients with hepatitis C virus genotype 1, which is known to be refractory to antiviral therapy. CONCLUSIONS: In summary, we observed that additional use of vitamin D has a positive effect on sustained viral response rates of patients with chronic hepatitis C infection. However, we cannot establish the efficacy because of substantial heterogeneity, a small sample size and a low methodological quality.
Subject(s)
Antiviral Agents/therapeutic use , Dietary Supplements , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Vitamin D/therapeutic use , Vitamins/therapeutic use , Adult , Aged , Antiviral Agents/pharmacology , Child , Female , Humans , Interferon-alpha/pharmacology , Interferon-alpha/therapeutic use , Male , Middle Aged , Ribavirin/pharmacology , Ribavirin/therapeutic use , Vitamin D/pharmacology , Vitamins/pharmacologyABSTRACT
Survival and proliferation of cancer cells are often associated with hyperactivity of the serine/threonine kinase, Akt. Herein, we show that prosurvival activity of Akt can be converted into prodeath activity by embedding an Akt recognition sequence in the apoptogenic BH3 domain of human BIM. The recognition sequence was created by introducing two mutations, I155R and E158S, into the core region of the BIM BH3 domain. Although a 21-mer BIM BH3 peptide containing these two mutations bound weakly to BCL-XL and BCL-2, this peptide with phosphorylation of Ser158 bound to these proteins with a dissociation constant of <10 nM. The crystal structure of the phosphorylated peptide bound to BCL-XL revealed that the phospho-Ser158 makes favorable interactions with two BCL-XL residues, which cannot be formed with unphosphorylated Ser158. Remarkably, the designed peptide showed a cytotoxic effect on PTEN-null PC3 tumor cells whose Akt activity is aberrantly high. The cell-killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression. Thus, these results lay a foundation for developing a peptide or protein agent that is dormant in normal cells but is transformed into a potent apoptogenic molecule upon phosphorylation by hyperactivity of Akt in cancer cells.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , Membrane Proteins/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins/genetics , bcl-X Protein/genetics , Bcl-2-Like Protein 11 , Binding Sites/genetics , Cell Proliferation/genetics , Cell Survival/genetics , HEK293 Cells , Humans , Neoplasms/genetics , Phosphorylation , Protein Binding , Protein Structure, TertiaryABSTRACT
We retrospectively investigated whether palonosetron administered during the induction of general anesthesia is associated with an increased risk of perioperative cardiovascular complications in a single tertiary center cohort consisting of 4,517 palonosetron-exposed patients and 4,517 propensity score-matched patients without palonosetron exposure. The primary endpoint was a composite of perioperative cardiovascular complications, including intraoperative cardiac arrhythmia, intraoperative cardiac death, and myocardial injury within the first postoperative week, and there was no significant difference between the groups (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 0.92-1.19). As secondary endpoints, intraoperative cardioversion, cardiac compression, use of cardiovascular drugs, postoperative hospital stay, and in-hospital mortality showed no differences between the groups. However, the palonosetron group showed decreased intraoperative hypotension (OR = 0.88; 95% CI = 0.79-0.97) and length of postoperative intensive care unit (ICU) stay (4.26 ± 9.86 vs. 6.14 ± 16.75; P = 0.026). Palonosetron did not increase the rate of perioperative cardiovascular complications, and can therefore be used safely during anesthetic induction.
Subject(s)
Anesthesia, General , Antiemetics/adverse effects , Cardiovascular System/drug effects , Isoquinolines/adverse effects , Quinuclidines/adverse effects , Serotonin 5-HT3 Receptor Antagonists/adverse effects , Adult , Aged , Arrhythmias, Cardiac/chemically induced , Case-Control Studies , Female , Humans , Male , Middle Aged , Myocardial Infarction/chemically induced , Palonosetron , Perioperative Period , Retrospective StudiesABSTRACT
OBJECTIVE: To evaluate whether statin use affects the development of tuberculosis (TB) among patients with diabetes mellitus (DM). METHODS: This is a retrospective cohort study of patients with newly diagnosed type 2 DM based on the South Korean nationwide claims database. The participants were type 2 DM patients aged 20-99 years who were newly treated with anti-diabetic drugs between 1 January 2007 and 31 December 2010. Patients who had statin prescriptions before a diagnosis of diabetes or were diagnosed with TB before diabetes were excluded. RESULTS: Of 840,899 newly diagnosed type 2 DM patients, 281,842 (33.5%) patients were statin users and 559,057 (66.5%) were non-users. During the study period, 4075 [corrected] individuals were diagnosed with TB; the estimated incidence of TB in our cohort was 251/100,000 patient-years (95%CI 243-258). In comparison to non-TB patients, statin users were less frequent among TB patients (19.2% vs. 33.6%). After adjustment for potential baseline confounders, statin use was not associated with the development of TB in DM patients (aHR 0.98; 95%CI 0.89-1.07). CONCLUSIONS: TB development among newly diagnosed type 2 DM was considerable, and statin use among these diabetics was not associated with a protective effect on TB incidence.
Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Tuberculosis/epidemiology , Adult , Aged , Aged, 80 and over , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hypoglycemic Agents/therapeutic use , Incidence , Male , Middle Aged , Protective Factors , Republic of Korea/epidemiology , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Tuberculosis/diagnosis , Young AdultABSTRACT
AIM: Leukoaraiosis and high intraocular pressure are strongly associated with cardiovascular disease, vascular angiopathy, and geriatric syndrome. Until now, little is known about the relationship between intraocular pressure and leukoaraiosis in its preclinical stage. The aim of this study was to evaluate the association between intraocular pressure and leukoaraiosis among middle-aged and elderly Koreans without glaucoma or dementia. METHODS: We examined the relationship of intraocular pressure with leukoaraiosis at a preclinical stage in 753 Korean adults (474 men, 279 women; mean age 57.8 ± 6.6 years). A multiple logistic regression analysis was performed in order to determine whether intraocular pressure is an independent determinant for leukoaraiosis. RESULTS: The overall prevalence of leukoaraiosis was 7.3%. Mean ocular pressure (±SD) was significantly higher in the leukoaraiosis group than the control group (14.3 ± 2.9 and 13.5 ± 2.9, respectively; P=0.028). In multiple logistic regression analysis, the odds ratio for leukoaraiosis was 1.18 (95% confidence interval: 1.06-1.31) for each 1 mm Hg increase in intraocular pressure. CONCLUSION: Intraocular pressure was found to be independently and positively associated with leukoaraiosis. This finding indicates that higher intraocular pressure may be a useful additional measure in assessing the risk of leukoaraiosis in the clinical setting.
Subject(s)
Intraocular Pressure/physiology , Leukoaraiosis/physiopathology , Aged , Asian People/ethnology , Dementia/physiopathology , Female , Glaucoma/physiopathology , Humans , Korea/epidemiology , Leukoaraiosis/diagnosis , Leukoaraiosis/ethnology , Magnetic Resonance Imaging , Male , Middle Aged , Odds Ratio , Retrospective Studies , Tonometry, OcularABSTRACT
BACKGROUND: Although chemotherapeutic regimens containing a taxane or platinum agent have been widely recommended for unfavourable carcinoma of unknown primary (CUP), no evidence exists for the superiority of any administered regimens. To date, the efficacy has been mostly assessed in the limited setting of phase II trials, and few attempts have been made to synthesise all available data for survival outcomes. METHODS: Electronic databases were searched from 1980 to 2011. Survival results were combined for each pre-specified category of regimens using a random-effects model, and meta-regression models were used to adjust for heterogeneity in some known prognostic factors. RESULTS: A total of 32 studies were included for meta-analysis. Tendency towards better survival outcome by platinums or taxanes was indicated. After adjustment for important prognostic factors, however, the difference between the platinum-based and non-platinum regimens became no longer significant. Survival benefits by the taxane-based regimens remained significant, with a prolonged median survival time of 1.52 months (P=0.03) and a higher 1-year survival rate of 6.25% (P=0.05), but the benefit did not sustain for 2 years. CONCLUSION: Although no effective therapies have been established, this meta-analysis helps to fill an important gap of evidence. However, caution should still be taken because of the potential unmeasured confounding.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms, Unknown Primary/drug therapy , Platinum Compounds/therapeutic use , Taxoids/therapeutic use , Drug Administration Schedule , Humans , Neoplasms, Unknown Primary/mortality , Prognosis , Survival AnalysisABSTRACT
BACKGROUND AND AIMS: Several studies demonstrated that reading nutrition labels was associated with healthier food choices, despite some controversy. This study investigated the association between the use of nutrition labels and metabolic syndrome (MetS) in Korean adults. METHODS AND RESULTS: This cross-sectional study included 7756 individuals who participated in the 2007-2009 Korean National Health and Nutrition Examination Survey (KNHANES). A self-reported questionnaire was used to determine participant's awareness of nutrition labels. Modified Asian criteria based on a harmonizing definition of MetS were adopted. Individuals in the group that read nutrition labels (the Reading Group) were youngest and leanest, but their daily caloric intake fell between that of the group that did not read nutrition labels (the Non-Reading Group) and the group that did not know about them (the Not-Knowing Group). The prevalence of MetS was 16.8% in the Reading Group, 27.2% in the Non-Reading Group, and 47.3% in the Not-Knowing Group. In comparison to participants in the Reading Group, the odds ratios (95% confidence interval) for MetS in the participants in the Non-Reading Group and Not-Knowing Group were 1.85 (1.60-2.14) and 4.44 (3.79-5.20), respectively, when not adjusted. The relationship between the use of nutrition labels and MetS remained statistically significant even after adjusting for covariates such as age, sex and socioeconomic status including household income and education level [1.27 (1.05-1.53) in the Non-Reading Group and 1.34 (1.05-1.70) in the Not-Knowing Group]. CONCLUSION: Reading nutrition labels appeared to be associated with a lower prevalence of MetS in a nationally representative sample of Korean adults.
Subject(s)
Food Labeling , Health Knowledge, Attitudes, Practice , Metabolic Syndrome/epidemiology , Metabolic Syndrome/prevention & control , Adult , Aged , Asian People , Blood Glucose , Body Mass Index , Cross-Sectional Studies , Female , Humans , Insulin/blood , Insulin Resistance , Life Style , Logistic Models , Male , Middle Aged , Motor Activity , Nutrition Surveys , Odds Ratio , Prevalence , Republic of Korea/epidemiology , Risk Factors , Socioeconomic FactorsABSTRACT
BACKGROUND: It has been observed that non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease and insulin resistance. Pulmonary function is also known to be related with cardiovascular disease and metabolic syndrome. AIMS: The objective of this study was to investigate the association between NAFLD and pulmonary function. METHODS: We performed a cross-sectional study to examine the association of NAFLD based on abdominal sonographic findings and pulmonary function in 2119 Korean men between the ages of 30 and 75. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) were compared according to the presence of NAFLD. Univariate and multivariate logistic regression analyses were conducted to evaluate the relationship of NAFLD with FVC and FEV(1) as pulmonary function tests. RESULTS: The subjects with NAFLD had lower FVC and FEV(1) than their non-steatotic counterparts, and FVC and FEV(1) gradually decreased according to the grade of hepatic steatosis. After adjusting for age, body mass index, smoking status, blood pressure, fasting plasma glucose, total cholesterol, hypertension, diabetes, triglyceride and high-density lipoprotein cholesterol, the FVC and FEV(1) were found to be inversely associated with the presence of NAFLD. CONCLUSION: NAFLD was independently associated with reduced pulmonary function, and the severity of NAFLD was inversely correlated with pulmonary function.
Subject(s)
Fatty Liver/epidemiology , Fatty Liver/physiopathology , Lung/physiology , Respiratory Function Tests/methods , Adult , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/physiopathology , Cross-Sectional Studies , Fatty Liver/diagnosis , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease , Respiratory Physiological Phenomena , Risk Factors , Surveys and Questionnaires , Vital Capacity/physiologyABSTRACT
DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-ß signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-ß can contribute to cancer progression through transcriptional target genes, such as Snail, MMPs, and epithelial-mesenchymal transition (EMT)-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-ß signaling-independent advantage, which should be essential for cancer cell survival. Here, we provide the evidences about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4-deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that Siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 renders the resistance to serum-deprivation-induced cell death, which is the TGF-ß-independent tumor suppressive role of Smad4.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis , Proto-Oncogene Proteins/metabolism , Smad4 Protein/metabolism , p21-Activated Kinases/metabolism , Cadherins/metabolism , Cell Line, Tumor , Culture Media, Serum-Free , Humans , Nuclear Proteins/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Signal Transduction , Smad4 Protein/antagonists & inhibitors , Smad4 Protein/physiology , Transforming Growth Factor beta/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
OBJECTIVES: Short-acting nifedipine is frequently prescribed in elderly hypertensive patients, despite warnings of possible harmful cardiovascular effects. We conducted a case-crossover study to estimate the risk of stroke episodes associated with use of short-acting nifedipine in elderly hypertensive patients. METHODS: We used the Korea Health Insurance Review & Assessment Service database. Cases included elderly hypertensive patients with hospitalization or emergency department visits for first stroke (International Classification of Diseases-10, I60-I64) between July 1, 2005, and June 30, 2006. Patients with prior stroke-related hospital admission or any visit related to TIA were excluded. Exposure to a short-acting nifedipine formulation was assessed within 7 days before the incident stroke episode (case period) and within a 7-day period preceding 60 days before the episode (control period). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by conditional logistic regression, with adjusting for antihypertensives, anticoagulants, antiplatelet agents, and pneumonia. RESULTS: A total of 16,069 stroke patients with a mean (±SD) age of 68.3 (±2.1) years were studied, of whom 8,573 (53.3%) were female. Short-acting nifedipine was prescribed at least once to 301 (1.9%) patients during the case period. An increased risk of stroke associated with use of short-acting nifedipine within 7 days (adjusted OR 2.56; 95% CI 1.96-3.37) was observed. Patients who were newly prescribed nifedipine within the recent 7 days showed an OR of 4.17 (95% CI 2.93-5.93) compared with nonusers. CONCLUSION: Use of short-acting nifedipine was associated with increased risk of stroke occurrence in elderly hypertensive patients.
Subject(s)
Nifedipine/therapeutic use , Stroke/drug therapy , Stroke/epidemiology , Vasodilator Agents/therapeutic use , Aged , Aged, 80 and over , Confidence Intervals , Cross-Over Studies , Female , Hospitalization/statistics & numerical data , Humans , Male , National Health Programs/statistics & numerical data , Odds Ratio , Republic of Korea/epidemiology , Retrospective Studies , Risk Factors , Time FactorsABSTRACT
OBJECTIVE: To provide scientific evidence supporting the efficacy of forest bathing as a natural therapy by investigating its physiological benefits using biological indicators in outdoor settings. STUDY DESIGN: Within-group comparisons were used to examine psychological and physiological responses to exposure to real forest and urban environments. METHODS: Young Japanese male adults participated in a 3-day, 2-night field experiment. Physiological responses as well as self-reported psychological responses to forest and urban environmental stimuli were measured in real settings. The results of each indicator were compared against each environmental stimulus. RESULTS: Heart rate variability analysis indicated that the forest environment significantly increased parasympathetic nervous activity and significantly suppressed sympathetic activity of participants compared with the urban environment. Salivary cortisol level and pulse rate decreased markedly in the forest setting compared with the urban setting. In psychological tests, forest bathing significantly increased scores of positive feelings and significantly decreased scores of negative feelings after stimuli compared with the urban stimuli. CONCLUSION: Physiological data from this field experiment provide important scientific evidence on the health benefits of forest bathing. The results support the concept that forest bathing has positive effects on physical and mental health, indicating that it can be effective for health promotion. Despite the small sample size in this study, a very clear tendency towards positive physiological and psychological outcomes in forests was observed.
Subject(s)
Autonomic Nervous System/physiology , Emotions/physiology , Trees , Adolescent , Environment , Environmental Monitoring/methods , Heart Rate/physiology , Humans , Hydrocortisone/analysis , Japan , Male , Mental Health , Monitoring, Ambulatory , Physiological Phenomena , Rural Population , Saliva/chemistry , Urban Population , Young AdultABSTRACT
p53 is frequently mutated by genetic alternation or suppressed by various kinds of cellular signaling pathways in human cancers. Recently, we have revealed that p53 is suppressed and eliminated from cells by direct binding with oncogenic K-Ras-induced Snail. On the basis of the fact, we generated specific inhibitors against p53-Snail binding (GN25 and GN29). These chemicals can induce p53 expression and functions in K-Ras-mutated cells. However, it does not show cytotoxic effect on normal cells or K-Ras-wild-type cells. Moreover, GN25 can selectively activate wild-type p53 in p53(WT/MT) cancer cells. But single allelic mt p53 containing cell line, Panc-1, does not respond to our chemical. In vivo xenograft test also supports the antitumor effect of GN25 in K-Ras-mutated cell lines. These results suggest that our compounds are strong candidate for anticancer drug against K-Ras-initiated human cancers including pancreatic and lung cancers.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Genes, ras/genetics , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Neoplasms/drug therapy , Neoplasms/pathology , Transcription Factors/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic , Child , Drug Evaluation, Preclinical , Female , Humans , Mice , Mutation , Neoplasms/genetics , Protein Binding/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Snail Family Transcription Factors , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The ability to predict poor outcome is important for patient care and treatment decision-making in cases of intracerebral hemorrhage (ICH). Previous studies have included relatively brief follow-up periods and small numbers of patients, and are limited in terms of considerations regarding individual brain vulnerabilities. METHODS: The authors prospectively enrolled 1,321 ICH patients nationwide from 33 hospitals. Clinical, laboratory, and imaging variables, including white matter lesions (WMLs), were collected at admission. Immediate outcome after ICH was measured using total Glasgow Coma Scale (GCS) score at admission, early outcome using 30-day mortality, and long-term outcome using relative risk for mortality. The vital status of included patients was ascertained on December 31, 2006, using Korean National Death Certificates (mean follow-up, 32.6 months). RESULTS: Of the 1,321 ICH patients included, 352 (27.8%) presented with a moderate GCS score (8.5-12.4) and 249 (19.7%) with a severe GCS score (=8.4). The mortality rate was 9.1% at day 30 post-ICH and 381 patients (29.8%) had died up to the end of December 2006. Extensive WMLs were associated with severe GCS scores at admission (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.73-3.46), 30-day mortality (OR 2.52, 95% CI 1.33-4.75), and the relative risk for mortality (RR 2.61, 95% CI 1.79-3.82) after adjusting for relevant covariates. CONCLUSIONS: These findings suggest that white matter lesions, which may reflect the vulnerability of individual brains to pathologic insults, should be considered when assessing immediate, early, and long-term outcomes after intracerebral hemorrhage.
Subject(s)
Brain/pathology , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/mortality , Nerve Fibers, Myelinated/pathology , Outcome Assessment, Health Care/methods , Aged , Brain/blood supply , Brain/physiopathology , Brain Mapping/methods , Cerebral Hemorrhage/physiopathology , Cohort Studies , Disability Evaluation , Female , Glasgow Coma Scale , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Mortality , Predictive Value of Tests , Prognosis , Prospective Studies , Republic of Korea/epidemiology , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
The epithelial to mesenchymal transition (EMT) that occurs during embryonic development has begun to attract attention as a potential mechanism for tumor cell metastasis. Snail is a well-known Zn-finger transcription factor that promotes EMT by repressing E-cadherin expression. It is known that Snail is phosphorylated by GSK3beta and degraded by beta-TrCP-mediated ubiquitination. Here we described another protein kinase, CK1, whose phosphorylation of Snail is required for the subsequent GSK3beta phosphorylation. Specific inhibition or depletion of CK1varepsilon inhibits the phosphorylation and degradation of Snail and promotes cell migration, suggesting a central role of CK1varepsilon in the EMT process. Furthermore, our study uncovered distinct roles and steps of Snail phosphorylation by CK1varepsilon and GSK3beta. Taken together, we identified CK1varepsilon as a new component of the Snail-mediated EMT process, providing insight into the mechanism of human cancer metastasis.
Subject(s)
Glycogen Synthase Kinase 3/metabolism , Transcription Factors/metabolism , Binding Sites , Creatine Kinase/metabolism , Glutathione Transferase/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Isoenzymes/metabolism , Kinetics , Phosphorylation , Phosphoserine/metabolism , RNA, Small Interfering/metabolism , Snail Family Transcription Factors , Substrate Specificity , beta-Transducin Repeat-Containing Proteins/metabolismABSTRACT
AIMS/HYPOTHESIS: Admission hyperglycaemia is associated with a poor outcome in patients with ischaemic stroke. However, its prognostic effects after intracerebral haemorrhage (ICH) are still unclear. METHODS: We prospectively enrolled patients with ICH at 33 centres in Korea between October 2002 and March 2004. A total of 1,387 patients who had ICH and underwent brain computed tomography within 48 h of symptom onset were included in the study (n = 1,387). Clinical information and radiological findings were collected at admission. Glucose levels were examined in relation to early (up to 30 days after ictus) and long-term (after 30 days) mortality rates using Cox regression analysis. To eliminate short-term effects, long-term mortality rate analysis was performed on surviving patients for more than 30 days. RESULTS: The long-term mortality rate was 21.1% after a mean follow-up of 434.3 +/- 223.2 days and was found to increase significantly with glucose quartile (p < 0.001). Admission glucose level was an independent risk factor for early mortality (per mmol/l; adjusted HR 1.10 [95% CI 1.01-1.19]), but not for long-term mortality. Moreover, when analysis was restricted to patients without diabetes, glucose level was found to be an independent risk factor for post-ICH mortality (n = 1,119; adjusted HR 1.10 [95% CI 1.03-1.17]) and had marginal significance for early (p = 0.053) and long-term mortality (p = 0.09). CONCLUSIONS/INTERPRETATION: We found that admission glucose levels were associated with early mortality after ICH. In patients without diabetes, admission glucose levels were associated with long-term mortality. We therefore suggest that intensive lowering of glucose level should be further investigated in ICH patients.
Subject(s)
Blood Glucose/metabolism , Cerebral Hemorrhage/blood , Cerebral Hemorrhage/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Korea , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk Factors , Treatment OutcomeABSTRACT
OBJECTIVE: The effects of granulocyte-colony stimulating factor (G-CSF) on endothelial function are unknown. Therefore, we investigated the effects of G-CSF on endothelial function. METHODS: 76 patients participating in the MAGIC-Cell-3-DES trial were enrolled. These were patients with acute myocardial infarction (AMI) or old MI (OMI) who underwent percutaneous coronary intervention (PCI), and were prospectively randomised into a G-CSF group (G-CSF (10 microg/kg/day) injection for 3 days after PCI) or a control group. Additionally, 20 healthy volunteers were also enrolled. These subjects were categorised into five groups: AMI-control (n = 18), AMI-G-CSF (18), OMI-control (20), OMI-G-CSF (20) and healthy-G-CSF (20). Baseline flow-mediated dilation (FMD) of the brachial artery and serum inflammatory biomarkers were performed on day 1, and repeated on day 4 in all groups. G-CSF was injected for 3 days between days 1 and 4 in the AMI-G-CSF, OMI-G-CSF and healthy-G-CSF groups. RESULTS: In both the healthy-G-CSF and OMI-G-CSF groups, G-CSF increased serum high sensitivity C-reactive protein (hsCRP) (0.3 (0.5) mg/l vs 6.1 (3.5) mg/l and 5.6 (3.8) mg/l vs 13.0 (7.7) mg/l, baseline vs post-G-CSF in the healthy and OMI-G-CSF groups, respectively, p<0.001). In the AMI-G-CSF group, G-CSF hindered the decline of hsCRP during the recovery phase, resulting in a relative increase in hsCRP. However, in all three groups, G-CSF did not significantly alter FMD. CONCLUSION: Despite an associated increase in systemic inflammation, G-CSF treatment does not lead to acute impairment of brachial artery endothelial function in either healthy subjects or patients with MI.