Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target.

Androgen-independent metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike a majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have shown a potential novel target, TWIST, a highly conserved bHLH transcription factor, in the treatment of prostate cancer. Using malignant and nonmalignant prostate tissues, we found that TWIST expression was highly expressed in the majority (90%) of prostate cancer tissues but only in a small percentage (6.7%) of benign prostate hyperplasia. In addition, the TWIST expression levels were positively correlated with Gleason grading and metastasis, indicating its role in the development and progression of prostate cancer. Furthermore, down-regulation of TWIST through small interfering RNA in androgen-independent prostate cancer cell lines, DU145 and PC3, resulted in increased sensitivity to the anticancer drug taxol-induced cell death which was associated with decreased Bcl/Bax ratio, leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed migration and invasion abilities of androgen-independent prostate cancer cells, which was correlated with induction of E-cadherin expression as well as morphologic and molecular changes associated with mesenchymal to epithelial transition. These results were further confirmed on the androgen-dependent LNCaP cells ectopically expressing the TWIST protein. Our results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene.

Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF).

Androgen-independent metastatic prostate cancer is the main cause of cancer related death in men. One of the reasons for this is the lack of understanding of the molecular mechanisms leading to the metastatic progression of prostate cancer. In this study, we have demonstrated that overexpression of Id-1 (inhibitor of differentiation/DNA synthesis), a member of the helix-loop-helix family proteins, is a key factor in promoting angiogenesis through activation of the vascular endothelial growth factor (VEGF) in prostate cancer cells. Using prostate cancer cells ectopically transfected with the Id-1 gene, we found that upregulation of Id-1 induced VEGF secretion through activation of the VEGF gene transcription. Downregulation of Id-1, however, led to the suppression of VEGF secretion and its gene promoter activity. The association between Id-1 and VEGF was also confirmed on human xenografts by immunohistochemical staining. In addition, the growth medium generated by the Id-1 expressing cells was able to promote morphological changes as well as capillary tube formation in human umbilical vein endothelial cells (HUVECs) at similar degrees to the recombinant human VEGF. Furthermore, inhibition of VEGF function by the treatment with an Flk-1 inhibitor, SU1498, or with the VEGF neutralizing antibody resulted in the reverse of the angiogenic effect on HUVECs. Our results suggest that overexpression of Id-1 in prostate cancer cells may provide an autocrine signal to promote angiogenesis through the activation of VEGF. Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through the suppression of angiogenesis.

Central clinical research issues in electrophysiology: report of the NASPE Committee.

This article contains the results of an attempt by appointed members of the North American Society of Pacing and Electrophysiology to define the research frontier in electrophysiology and suggest areas of study as an aid in setting the research agenda.

An abdominal active can defibrillator may facilitate a successful generator change when a lead failure is present.

AIMS: Defibrillator generator changes are frequently performed on patients with an implantable cardioverter defibrillator in an abdominal pocket. These patients usually have epicardial patches or older endocardial lead systems. At the time of a defibrillator generator change defibrillation may be unsuccessful as a result of lead failure. We tested the hypothesis that an active can defibrillator implanted in the abdominal pocket could replace a non-functioning endocardial lead or epicardial patch. METHODS AND RESULTS: An abdominal defibrillator generator change was performed in 10 patients, (mean age = 67 +/- 13 years, nine men). Initially, a defibrillation threshold (DFT) was obtained using a passive defibrillator and the chronic endocardial or epicardial lead system. DFTs were then performed using an active can emulator and one chronic lead to simulate endocardial or epicardial lead failure. We tested 30 lead configurations (nine endocardial and 21 epicardial). Although a DFT of 7.3 +/- 4.2 joules was obtained with the intact chronic lead system, the active can emulator and one endocardial or epicardial lead still yielded an acceptable DFT of 19.9 +/- 6.1 joules. In addition, a successful implant (DFT < or = 24 joules) could have been accomplished in 28 of 30 (93%) lead configurations. CONCLUSION: An active can defibrillator in an abdominal pocket may allow for a successful generator change in patients with defibrillator lead malfunction. This would be simpler than abandoning the abdominal implant and moving to a new pectoral device and lead or tunnelling a new endocardial electrode. However, loss of defibrillation capability with a particular complex lead may be a warning of impending loss of other functions (eg. sensing and/or pacing).

QT prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report.

BACKGROUND: The use of immunosuppressant agents is mandatory in the long-term management of transplant recipients. Herein, we report a case of near fatal cardiac arrhythmia related to the use of intravenous tacrolimus in a 35-year-old woman undergoing renal transplantation. METHODS: The patient had no previous history of cardiac disease, but an initial electrocardiogram demonstrated slightly prolonged QT and QTc intervals and normal sinus rhythm. Postsurgical immunosuppression included intravenous tacrolimus and methylprednisolone. During intravenous tacrolimus infusion, marked QT prolongation occurred. The patient suffered recurrent runs of torsade de pointes, refractory to aggressive medical management and requiring numerous defibrillations. Rapid atrial pacing eventually controlled the arrhythmia. RESULTS: We note not only a temporal association, but also a direct linear relationship, between this arrhythmia and blood tacrolimus levels. CONCLUSION: We believe this case presents a little recognized hazard associated with the use of intravenous tacrolimus and points to the need for careful predrug screening for QT prolongation. Tacrolimus has been shown to effect intracellular calcium and to prolong the action potential duration experimentally. This suggests that an increase in the intracellular calcium may underlie torsades de pointes associated with intravenous tacrolimus.

Catheter ablation for patients with atrial tachycardia.

Although atrial tachycardias are relatively rare, their poor response to standard therapies, the suboptimal hemodynamic results of complete atrioventricular node ablation and pacer implantation, and their potential for serious hemodynamic effects make management difficult. Although their mechanisms are complex and divergent, catheter ablation has proven to be highly effective in management of atrial tachycardias. This article discusses arrhythmia mechanisms and therapeutic approaches by catheter ablation.

Alterations in heart rate following radiofrequency ablation in the treatment of reentrant supraventricular arrhythmias: relation to alterations in autonomic tone.

To determine the relation between the creation of endocardial lesions and alterations in autonomic tone, we analyzed heart rate variability in patients undergoing radiofrequency catheter ablation for symptomatic supraventricular tachycardia. Elevated heart rates are frequently noted after radiofrequency catheter ablation for supraventricular arrhythmias. It has been postulated that this elevation may be secondary to alterations in cardiac autonomic tone. Since heart rate variability is a measure of autonomic nervous system activity, we used this technique to examine the heart rate elevation and to characterize postablation autonomic changes. Thirty-eight patients undergoing 44 radiofrequency catheter ablation procedures were included in the study. Total arrhythmic substrates treated included 34 accessory pathways and 13 AV nodes with dual physiology. Twenty-four hour ambulatory electrocardiographic recordings were obtained in a drug-free state prior to, ablation early postablation, and late postablation. Spectral and nonspectral analyses of heart rate variability were performed. Subgroup analyses were also done on specific cohorts. Subgroups included patients undergoing accessory pathway ablations, AV node modifications, and ablation of septal and nonseptal targets. To determine whether the amount of tissue damage was related to changes in heart rate variability, we analyzed the relation between the total energy delivered to the endocardium and the peak change in creatine kinase and heart rate variability. In this population, a significant transient increase in heart rate was noted following radiofrequency ablation. All time and frequency domain parameters of heart rate variability showed significant reversible decreases. These changes were independent of target site and arrhythmia substrate. There was no correlation noted between the changes in heart rate variability and either the total amount of energy applied to the endocardium or the change in creatine kinase. Increased heart rates and decreased heart rate variability occur following radiofrequency catheter ablation for supraventricular tachycardia. Clinically, the predominant effect is that of decreased parasympathetic tone. Since these transient changes are independent of arrhythmic substrate or ablation site in the atria, a rich parasympathetic innervation of the heart is proposed.

Successful ablation of a nonreentrant dual atrioventricular nodal tachycardia.

Selective radiofrequency catheter ablation of the slow pathway of the AV node has become the treatment of choice for AV nodal reentrant tachycardia. We describe a case of a nonreentrant AV nodal tachycardia and its successful treatment by slow pathway ablation.

Implantation of a nonthoracotomy defibrillator using a second defibrillator patch in the abdominal pocket.

Successful implantation of a biphasic nonthoracotomy implantable cardioverter defibrillator may not be achieved with a conventional system. We describe a successful device implantation using a pectoral and abdominal patch electrode system.

A second defibrillator chest patch electrode will increase implantation rates for nonthoracotomy defibrillators.

Nonthoracotomy defibrillator systems can be implanted with a lower morbidity and mortality, compared to epicardial systems. However, implantation may be unsuccessful in up to 15% of patients, using a monophasic waveform. It was the purpose of this study to prospectively examine the efficacy of a second chest patch electrode in a nonthoracotomy defibrillator system. Fourteen patients (mean age 62 +/- 11 years, ejection fraction = 0.29 +/- 0.12) with elevated defibrillation thresholds, defined as > or = 24 J, were studied. The initial lead system consisted of a right ventricular electrode (cathode), a left innominate vein, and subscapular chest patch electrode (anodes). If the initial defibrillation threshold was > or = 24 J, a second chest patch electrode was added. This was placed subcutaneously in the anterior chest (8 cases), or submuscularly in the subscapular space (6 cases). This resulted in a decrease in the system impedance at the defibrillation threshold, from 72.3 +/- 13.3 omega to 52.2 +/- 8.6 omega. Additionally, the defibrillation threshold decreased from > or = 24 J, with a single patch, to 16.6 +/- 2.8 J with two patches. These changes were associated with successful implantation of a nonthoracotomy defibrillator system in all cases. In conclusion, the addition of a second chest patch electrode (using a subscapular approach) will result in lower defibrillation thresholds in patients with high defibrillation thresholds, and will subsequently increase implantation rates for nonthoracotomy defibrillators.