Time Series Electrical Motor Drives Forecasting Based on Simulation Modeling and Bidirectional Long-Short Term Memory.

Accurately forecasting electrical signals from three-phase Direct Torque Control (DTC) induction motors is crucial for achieving optimal motor performance and effective condition monitoring. However, the intricate nature of multiple DTC induction motors and the variability in operational conditions present significant challenges for conventional prediction methodologies. To address these obstacles, we propose an innovative solution that leverages the Fast Fourier Transform (FFT) to preprocess simulation data from electrical motors. A Bidirectional Long Short-Term Memory (Bi-LSTM) network then uses this altered data to forecast processed motor signals. Our proposed approach is thoroughly examined using a comparative examination of cutting-edge forecasting models such as the Recurrent Neural Network (RNN), Long Short-Term Memory (LSTM), and Gated Recurrent Unit (GRU). This rigorous comparison underscores the remarkable efficacy of our approach in elevating the precision and reliability of forecasts for induction motor signals. The results unequivocally establish the superiority of our method across stator and rotor current testing data, as evidenced by Mean Absolute Error (MAE) average results of 92.6864 and 93.8802 for stator and rotor current data, respectively. Additionally, compared to alternative forecasting models, the Root Mean Square Error (RMSE) average results of 105.0636 and 85.7820 underscore reduced prediction loss.

RealPrice: Blockchain-Powered Real-Time Pricing for Software-Defined Enabled Edge Network.

With the limited Internet bandwidth in a given area, unlimited data plans can create congestion because there is no retribution for transmitting many packets. The real-time pricing mechanism can inform users of their Internet consumption to limit congestion during peak hours. However, implementing real-time pricing is opex-heavy from the network provider side and requires high-integrity operations to gain consumer trust. This paper aims to leverage the software-defined network to solve the opex issues and blockchain technology to solve trust issues. First, the network congestion level in a given area is analyzed. Then, the price is adjusted accordingly. Devices that send a lot of traffic during congestion will be charged more expensive bills than if transmitting traffic during an off-peak period. To prevent over-charging, the consumers can pre-configure a customized Internet profile stating how many data bytes they are willing to send during congestion. The software-defined controller also authenticates consumers and checks whether they have enough token deposits in the blockchain as Internet usage fees. We implement our work using Ethereum and POX controllers. The experiment results show that the proposed real-time pricing can be performed seamlessly, and the network provider can reap up to 72.91% more profits than existing approaches, such as usage-based pricing or time-dependent pricing. The fairness and trustability of real-time pricing is also guaranteed through the proof-of-usage mechanism and the transparency of the blockchain.

Complications of Cardiac Perforation and Lead Dislodgement with an MRI-Conditional Pacing Lead: a Korean Multi-Center Experience.

Medtronic CapSureFix MRI 5086 pacing lead (5086; Medtronic, Inc., Minneapolis, MN, USA) has been reported to be associated with increased cardiac perforation and lead dislodgement. This study aimed to compare the incidence of cardiac perforation and lead dislodgement within 30 days after pacemaker implantation between 5086 MRI lead and previous Medtronic CapSureFix Novus 5076 non-MRI pacing lead. This was a nationwide, multicenter retrospective study in which we compared the incidence of adverse events between 277 patients implanted with 5086 lead and 205 patients implanted with 5076 lead between March 2009 and September 2014. Cardiac perforation within 30 days of pacemaker implantation occurred in 4 patients (1.4%) with the 5086 lead and in no patient with the 5076 lead (P = 0.084). Lead dislodgement occurred in 8 patients (2.9%) with the 5086 lead and in 5 patients (2.4%) with the 5076 lead (P = 0.764). On multivariate logistic regression analysis, age was significantly associated with cardiac perforation. Congestive heart failure and implantation of right atrial (RA) lead at RA free wall or septum were significant factors for the incidence of lead dislodgement and lead revision. The incidence of cardiac perforation and lead dislodgement were not statistically different between the patients with 5086 lead and the patients with 5076 lead. However, careful attention for cardiac perforation may be needed when using the 5086 MRI lead, especially in elderly patients.

Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice.

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

APACHE II score, rather than cardiac function, may predict poor prognosis in patients with stress-induced cardiomyopathy.

While the disease course of stress-induced cardiomyopathy (SIC) is usually benign, it can be fatal. The prognostic factors to predict poorer outcome are not well established, however. We analyzed the Acute Physiology And Chronic Health Evaluation (APACHE) II score to assess its value for predicting poor prognosis in patients with SIC. Thirty-seven consecutive patients with SIC were followed prospectively during their hospitalization. Clinical factors, including APACHE II score, coronary angiogram, echocardiography and cardiac enzymes at presentation were analyzed. Of the 37 patients, 27 patients (73%) were women. The mean age was 66.1 ± 15.6 yr, and the most common presentation was chest pain (38%). Initial echocardiographic left ventricular ejection fraction (EF) was 42.5% ± 9.3%, and the wall motion score index (WMSI) was 1.9 ± 0.3. Six patients (16%) expired during the follow-up period of hospitalization. Based on the analysis of characteristics and clinical factors, the only predictable variable in prognosis was APACHE II score. The patients with APACHE II score greater than 20 had tendency to expire than the others (P = 0.001). Based on present study, APACHE II score more than 20, rather than cardiac function, is associated with mortality in patients with SIC.

The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population.

BACKGROUND: Human Epidermal Growth Factor Receptor 2 (HER-2; also known as erbB-2 or neu), a proto-oncogene of the receptor tyrosine kinase superfamily, has been associated with carcinogenesis and prognosis of human cancers, acting as a binding partner of other epidermal growth factor receptor (EGFR) family in the activation of EGFR signaling. Amplification of the HER-2 gene has been reported in lung cancer, where it has been associated with poor prognosis. In this study, we investigated whether the four polymorphisms (-3444C>T, -1985 G>T, I655A A>G and P1170A C>G) of the HER-2 gene are associated with the risk of lung cancer in Korean populations. METHODS: The frequencies of 4 polymorphisms of the HER-2 gene were examined by the polymerase chain reaction-restriction fragment length polymorphism or the single-nucleotide polymorphism-identification technology assay in the 407 lung cancer patients and 407 healthy controls. RESULTS: The frequencies of the 4 polymorphisms were not significantly different between patient and control groups in overall subjects. However, in the subgroup analysis, the 3 single nucleotide polymorphisms (-3444C>T, -1985G>T and P1170A C>G) showed statistically significant differences in the subgroups of females, non-smokers, and non-drinkers (p < 0.05). Additionally, we found the association between the risk of lung cancer and the polymorphisms of HER-2 gene in non-smoker subgroups with adenocarcinoma (p < 0.05). CONCLUSION: Our results suggest that the polymorphisms of the HER-2 gene are associated with an increased susceptibility to lung cancer in females, non-smokers and non-drinkers subgroups in the Korean population.

[Corrigendum] Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer.

Following the publication of this article, an interested reader drew to our attention that there were possible anomalies in the presentation of Fig. 5B in the above article. After having examined the figure, we recognized that several errors had indeed occurred during the process of compiling the figure. A corrected version of Fig. 5 is shown below, containing new data for Fig. 5B, after our having re-performed the western blot experiment according to the identical procedure detailed in the paper. We obtained broadly similar results to those featured originally in the article; therefore, the revision of this figure does not affect the conclusions reported in the study. We thank the reader of our article who drew this matter to our attention. [the original article was published in the International Journal of Oncology 41: 611-620, 2012; DOI: 10.3892/ijo.2012.1470].

Characteristics of early repolarization parameters and prognostic implications in the general ambulatory Korean population.

BACKGROUND: We tested a hypothesis that the 2 fundamental components of early repolarization (ER), J wave and ST elevation (STE) might have different prevalence and prognostic implications. METHODS: The study population comprised 26,345 general ambulatory Korean subjects (mean 48.0±10.2years old, 53.2% male) who underwent medical checkups from January 2002 to December 2002. ER was found in 2950 subjects (11.2%), who were divided into 3 groups (J [J wave only, n=1874, 7.1%], JST [both J wave and STE, n=489, 1.8%], and ST [STE only, n=587, 2.3%]). RESULTS: The prevalence of STE decreased with age, whereas J waves remained at a constant level in all age groups. The most common pattern of ER was the J pattern, with a horizontal/descending ST segment in the inferior leads; in lateral precordial leads, ST or JST patterns with ascending ST segments were more common. During the mean follow-up of 126.0±11.1months, a total of 710 subjects died (2.7%). Subjects in the J group were at higher risk (Hazard ratio 1.60, 95% confidence interval 1.27-2.01, p<0.001), while those in the JST and ST groups showed similar survival outcomes compared to controls without J waves or STE. CONCLUSIONS: J waves and STE showed different age and lead distributions and prognostic implications. The presence of the J wave itself was associated with a higher relative risk of mortality. However, due to the low event rate, its clinical significance appears to be limited.

Tachyarrhythmia Cycle Length in Appropriate versus Inappropriate Defibrillator Shocks in Brugada Syndrome, Early Repolarization Syndrome, or Idiopathic Ventricular Fibrillation.

BACKGROUND AND OBJECTIVES: Implantable cardioverter-defibrillators (ICDs) are indicated in patients with Brugada syndrome (BS), early repolarization syndrome (ERS), or idiopathic ventricular fibrillation (IVF) who are at high risk for sudden cardiac death. The optimal ICD programming for reducing inappropriate shocks in these patients remains to be determined. We investigated the difference in the mean cycle length of tachyarrhythmias that activated either appropriate or inappropriate ICD shocks in these three patient groups to determine the optimal ventricular fibrillation (VF) zone for minimizing inappropriate ICD shocks. SUBJECTS AND METHODS: We selected 41 patients (35 men) (mean age±standard deviation=42.6±13.0 year) who received ICD shocks between April 1996 and April 2014 to treat BS (n=24), ERS (n=9), or IVF (n=8). Clinical and ICD interrogation data were retrospectively collected and analyzed for all events with ICD shocks. RESULTS: Of the 244 episodes, 180 (73.8%) shocks were appropriate and 64 (26.2%) were inappropriate. The mean cycle lengths of the tachyarrhythmias that activated appropriate and inappropriate shocks were 178.9±28.7 ms and 284.8±24.4 ms, respectively (p<0.001). The cutoff value with the highest sensitivity and specificity for discriminating between appropriate and inappropriate shocks was 235 ms (sensitivity, 98.4%; specificity, 95.6%). When we programmed a single VF zone of ≤270 ms, inappropriate ICD shocks were reduced by 70.5% and appropriate shocks were missed in 1.7% of these patients. CONCLUSION: Programming of a single VF zone of ≤270 ms in patients with BS, ERS, or IVF could reduce inappropriate ICD shocks, with a low risk of missing appropriate shocks.

Clinical, Echocardiographic, and Electrocardiographic Predictors of Persistent Atrial Fibrillation after Dual-Chamber Pacemaker Implantation: An Integrated Scoring Model Approach.

Persistent atrial fibrillation (PeAF) predictors after dual-chamber pacemaker (PM) implantation remain unclear. We sought to determine these predictors and establish an integrated scoring model. Data were retrospectively reviewed for 649 patients (63.8 ± 12.3 years, 48.6% male, mean CHA2DS2-VASC score 2.7 ± 2.0) undergoing dual-chamber PM implantation. PeAF was defined as documented AF on two consecutive electrocardiograms acquired ≥7 days apart. During a 7.1-year median follow-up (interquartile range 4.5-10.1 years), 67 (10.3%) patients had PeAF. Multivariable analysis showed the following independent predictors of future PeAF: ischemic stroke or transient ischemic accident history (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.03-3.50, p = 0.040), atrial fibrillation/flutter history (HR 1.80, 95% CI 1.01-3.20, p = 0.046), sinus node disease (HR 2.24, 95% CI 1.16-4.35, p = 0.016), left atrial enlargement (>45 mm, HR 2.14, 95% CI 1.26-3.63, p = 0.005), and time in automatic mode switching >1% at first follow-up interrogation (HR 2.58, 95% CI 1.51-4.42, p < 0.001). An integrated scoring model combining these predictors showed good discrimination performance at the seven-year follow-up. (C-statistic 0.716, 95% CI 0.629-0.802, p < 0.001). Significantly greater seven-year PeAF incidences were seen in patients with higher scores (2-5) than in those with lower scores (0-1) (22.8% ± 3.8% vs. 5.3% ± 1.7%, p < 0.001). In conclusion, an integrated scoring model combining clinical, echocardiographic, and electrocardiographic characteristics is useful for predicting future PeAF in patients with a dual-chamber PM.

Transvenous Lead Extraction via the Inferior Approach Using a Gooseneck Snare versus Simple Manual Traction.

BACKGROUND AND OBJECTIVES: The number of patients with cardiac implantable electronic devices needing lead extraction is increasing for various reasons, including infections, vascular obstruction, and lead failure. We report our experience with transvenous extraction of pacemaker and defibrillator leads via the inferior approach of using a gooseneck snare as a first-line therapy and compare extraction using a gooseneck snare with extraction using simple manual traction. SUBJECTS AND METHODS: The study included 23 consecutive patients (43 leads) who underwent transvenous lead extraction using a gooseneck snare (group A) and 10 consecutive patients (17 leads) who underwent lead extraction using simple manual traction (group B). Patient characteristics, indications, and outcomes were analyzed and compared between the groups. RESULTS: The dwelling time of the leads was longer in group A (median, 121) than in group B (median, 56; p=0.000). No differences were noted in the overall procedural success rate (69.6% vs. 70%), clinical procedural success rate (82.6% vs. 90%), and lead clinical success rate (86% vs. 94.1%) between the groups. The procedural success rates according to lead type were 89.2% and 100% for pacing leads and 66.7% and 83.3% for defibrillator leads in groups A and B, respectively. Major complications were noted in 3 (mortality in 1) patients in group A and 2 patients in group B. CONCLUSION: Transvenous extraction of pacemaker leads via an inferior approach using a gooseneck snare was both safe and effective. However, stand-alone transvenous extraction of defibrillator leads using the inferior approach was suboptimal.

ECG features and proarrhythmic potentials of therapeutic hypothermia.

OBJECTIVE: Hypothermia can induce ECG J waves. Recent studies suggest that J waves may be associated with ventricular fibrillation (VF) in patients with structurally normal hearts. However, little is known about the ECG features, clinical significance or arrhythmogenic potentials of therapeutic hypothermia (TH)-induced J waves. METHODS: We analysed ECGs from 240 patients who underwent TH at six major university hospitals in Korea between August 2010 and December 2013. The prevalence, amplitudes and distributions of the J waves and the development of malignant arrhythmia were analysed. RESULTS: The average patient body temperature was 33.5±1.0°C during TH. J waves were observed in 98 patients (40.8%). They were newly developed in 91 cases, and pre-existing J waves were augmented in seven patients. J waves during TH were primarily observed in leads II, III, aVF and V4-6. The average amplitude of the J waves was 0.239±0.152 mV. There were four VF events during TH. These events occurred in three patients who were finally diagnosed with Brugada syndrome, idiopathic VF or early repolarisation syndrome, respectively, and in one patient with non-cardiac aetiology (asphyxia). CONCLUSIONS: J waves were recorded in about 40% of the patients who received TH. They were most frequently observed in the inferior limb leads or lateral precordial leads. Life-threatening VF occurred only rarely (1.7%) during TH and were mainly observed in patients with primary arrhythmic disorder. Although a causal relationship between TH-induced J waves and VF remains unknown, administering TH to this potentially susceptible, high-risk population may require careful attention.

Impact of Impaired Renal Function on the Incidence of Atrial Fibrillation following Radiofrequency Ablation of Cavotricuspid Isthmus-Dependent Atrial Flutter.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) occurs frequently after successful radiofrequency ablation (RFA) of cavotricuspid isthmus-dependent atrial flutter (CTI-AFL). Renal impairment has been implicated in the development of AF. The purpose of this study is to clarify the impact of impaired renal function on the incidence of AF after RFA of CTI-AFL. SUBJECTS AND METHODS: Between January 2001 and December 2013, 240 non-dialysis patients with no prior history of AF {mean age 55.9±15.2 years old; male, 192 (80.0%)} who had undergone successful CTI-AFL ablation were included in the present study. The baseline estimated glomerular filtration rate was calculated, and patients were divided into those with impaired renal function (<60 mL/min/1.73 m(2)) and those with preserved renal function (≥ 60 mL/min/1.73 m(2)). The incidence of AF was retrospectively analyzed. RESULTS: 69 (28.8%) patients experienced new onset AF during a median follow-up duration of 26 months (inter-quartile, 7-53). The incidence of AF was significantly higher in patients with impaired renal function than in those with preserved renal function {13/25 (52.0%) versus 56/215 (26.0%), log rank p=0.019}. Age, CHADS2 score, impaired renal function, and left atrial diameter were significantly associated with the incidence of AF in univariate Cox regression analysis. Multivariate analysis showed that age was the only significant predictor of AF incidence (hazard ratio, 1.024; 95% confidence interval, 1.004-1.044, p=0.020). CONCLUSION: Patients with impaired renal function may require careful attention for the incidence of new onset AF following successful RFA of CTI-AFL.

Can mutations of EGFR and KRAS in serum be predictive and prognostic markers in patients with advanced non-small cell lung cancer (NSCLC)?

The status of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations has been used widely in management of patients with non-small cell lung cancer (NSCLC). However, it may be difficult to get tumor tissues for analyzing the status of EGFR and KRAS mutation in large proportion of patients with advanced disease. We obtained pairs of tumor and serum samples from 57 patients with advanced NSCLC, between March 2006 and January 2009. EGFR mutation status from tumor samples and KRAS mutation status from serum samples were analyzed by genomic polymerase chain reaction and direct sequence, and EGFR mutation status from serum samples was determined by the peptide nucleic acid-locked nucleic acid PCR clamp. EGFR mutations were detected in the serum samples of 11 patients and in the tumor samples of 12 patients. Fourteen patients revealed (?) KRAS mutation in the serum sample. EGFR mutation status in the serum and tumor samples was consistent in 50 (87.7 %) of the 57 pairs (correlation index 0.62, p < 0.001). Only 5 of 57 (8.7 %) patients showed mutation of both EGFR and KRAS in serum sample. Twenty-two of 57 patients (38.5 %) received EGFR-TKIs as any line therapy. The response for EGFR-TKIs was significantly associated with EGFR mutations in both tumor samples and serum samples (p < 0.05). The status of KRAS mutation in serum was not predictive for the response of EGFR-TKI (p > 0.05). There was no significant difference in OS according to the status of EGFR mutations in both serum and tumor samples (p > 0.05) and KRAS mutations in serum samples (p > 0.05). The status of EGFR and KRAS mutation in serum was not prognostic in patients with advanced NSCLC. However, the clinical usefulness of EGFR mutation of serum as a selection marker for EGFR-TKIs sensitivity in NSCLC might be allowed, not KRAS mutation.

Can serum be used for analyzing the EGFR mutation status in patients with advanced non-small cell lung cancer?

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations as prognostic or predictive marker in patients with non-small cell lung cancer (NSCLC) have been used widely. However, it may be difficult to get tumor tissue for analyzing the status of EGFR mutation status in large proportion of patients with advanced disease. PATIENTS AND METHODS: We obtained pairs of tumor and serum samples from 57 patients with advanced NSCLC, between March 2006 and January 2009. EGFR mutation status from tumor samples was analyzed by genomic polymerase chain reaction and direct sequence and EGFR mutation status from serum samples was determined by the peptide nucleic acid locked nucleic acid polymerase chain reaction clamp. RESULTS: EGFR mutations were detected in the serum samples of 11 patients and in the tumor samples of 12 patients. EGFR mutation status in the serum and tumor samples was consistent in 50 of the 57 pairs (87.7%). There was a high correlation between the mutations detected in serum sample and the mutations detected in the matched tumor sample (correlation index 0.62; P<0.001). Twenty-two of 57 patients (38.5%) received EGFR-tyrosine kinase inhibitors as any line therapy. The response for EGFR-tyrosine kinase inhibitors was significantly associated with EGFR mutations in both tumor samples and serum samples (P<0.05). There was no significant differences in overall survival according to the status of EGFR mutations in both serum and tumor samples (P>0.05). CONCLUSIONS: Serum sample might be alternatively used in the difficult time of getting tumor tissue for analyzing the status of EGFR mutation status in patients with advanced NSCLC.

A case of possible neurosarcoidosis presenting as intractable headache and panhypopituitarism.

Sarcoidosis is a chronic multisystemic inflammatory disease of unknown etiology, which is characterized by noncaseating granulomatous inflammation of the involved organs. It is known that neurosarcoidosis involving the nervous system occurs in about 5% of patients with sarcoidosis. However, neurosarcoidosis without systemic involvement is extremely rare. We present a case of suspicious neurosarcoidosis affecting the pituitary gland, which was manifested as chronic uncontrolled headache, panhypopituitarism, central diabetes insipidus, and hypercalcemia. Though the biopsy at the pituitary lesion was not performed due to the high risk of surgical complication, treatment was needed urgently and we started steroid therapy. After steroid therapy, we observed the immediate symptom relief with improved hypercalcemia. According to the follow-up examination, no recurrent symptom was seen, and resolution of the pituitary lesion with improving panhypopituitarism was noted.

Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer.

Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.

Methylation of AKAP12{alpha} promoter in lung cancer.

AKAP12α plays an important role in tumour growth suppression by inducing apoptosis. This study investigated whether the promoter methylation of AKAP12α is associated with lung cancer. AKAP12α was down-regulated in lung cancer cells and the reduced protein expression was restored by DNA methyl-transferase inhibitor. AKAP12α promoter was more frequently methylated in tumours than in normal tissues. Furthermore, AKAP12α methylation was found more frequently in the cells of non-relapse patients after surgery than in those of early relapse patients. In conclusion, this study demonstrated that AKAP12α expression is regulated by DNA methylation and that AKAP12α promoter methylation is associated with lung cancer prognosis.

Microtubule-damaging agents enhance RASSF1A-induced cell death in lung cancer cell lines.

BACKGROUND: Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule-targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule-related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule-targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells. METHODS: The growth inhibitory effects of TXL and VCS on RASSF1A-transfected cells were assessed using clonogenic and flow cytometry-based propidium iodide-labeled assay. The levels of mitosis-related proteins in RASSF1A-transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay. RESULTS: RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS-2B) by inducing cell cycle arrest at the G2/M-phase. Accumulation of cyclin B1, G2/M-phase-related protein, was observed when RASSF1A-transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA. CONCLUSIONS: RSAAF1A protein has a cooperative growth inhibitory effect with microtubule-targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents.