Suitability of Metastatic Lung Tumors for Stereotactic Body Radiotherapy.

We investigated factors influencing local control of lung metastases treated with stereotactic body radiotherapy (SBRT) and determined the type of lesions for which SBRT is more suitable. Ninety-six patients and 196 tumors were included. Median follow-up duration was 32.0 months (range 4.7-95.8). The two-year local recurrence rate was 15.2% (95% confidence interval: 10.2-21.3). Multivariate analysis revealed biological effective dose, ultracentral tumor location, reirradiation, and prior chemotherapy as significant factors. SBRT is suitable for lung metastases, especially for peripheral tumors and those located in the inner lung parenchyma. For ultracentral lesions and recurrent lesions after SBRT, metastasectomy is recommended.

Dual scope method: A novel application of a simultaneous multi-image display system for a thoracoscopic robotic lobectomy.

The advantages of a multi-input display system platform in robotic thoracic surgery have not been well described. We report the novel application of a multi-display system for simultaneous visualization of an additional thoracoscopic image during a robotic lobectomy, which we have named the dual scope method. An additional thoracoscope is inserted from the bottom of the thoracic cavity. This thoracoscope visualizes the whole operative field, including the robot arms, from a bystander's viewpoint. By providing an integrated image from the robot scope and the thoracoscope, various problems, such as arm collision, inappropriate instrument direction, excessive traction, and injury, can be solved or avoided much more easily and safely than with the use of the robotic image alone. The dual scope method facilitates the safety and efficiency of robotic lobectomy.

Stapling of an endobronchial suction tube with the bronchus during robot-assisted right lower lobectomy: a case report.

BACKGROUND: Troubleshooting intraoperative complications requires careful management, and the safest technique should be chosen. We recently experienced a unique intraoperative bronchial complication during pulmonary lobectomy in robot-assisted thoracic surgery (RATS). There is no consensus on whether to continue RATS or convert to a more familiar technique, such as video-assisted thoracic surgery (VATS) or thoracotomy, for intraoperative complications that occur during RATS, and the decision should be determined individually. CASE PRESENTATION: A 74-year-old woman with primary lung adenocarcinoma (clinical stage IA2) underwent robot-assisted right lower lobectomy under one-lung ventilation and CO2 insufflation. Intraoperatively, the anesthesiologist placed the endobronchial suction tube in the right bronchus with intention of maintaining the right lung collapse, which was simultaneously stapled with the right lower bronchus during the right lower lobe bronchial closure using a robotic stapler. During robot-assisted manipulation, we removed the staples involved with the suction tube, one by one, using robotic-arm forceps and sutured the partially opened stump. Subsequently, the bronchial stump was covered with a pedicled pericardial fat pad. The postoperative course was uneventful, and the patient developed no complications when followed up 8 months after discharge. Hence, we could rectify this intraoperative bronchial complication using a robot-assisted technique and avoid conversion to VATS or thoracotomy. CONCLUSION: The precise manipulation techniques in RATS contributed to facilitate the successful execution of surgical procedures, such as staple removal and re-suturing of the bronchial stump and may be a useful as a method for such troubleshooting such intraoperative complications.

The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: A non-randomized prospective interventional study.

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ±â€Š.04 mg/kg [mean ±â€Šstandard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ±â€Š.31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ±â€Š32.3 ng/mL in 7 responders and was significantly higher than 29.5 ±â€Š23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

Granulomatous-lymphocytic Interstitial Lung Disease Associated with Good's Syndrome That Responded to Immunoglobulin Therapy.

Good's syndrome is associated with thymoma and acquired immunodeficiency. A 54-year-old man visited our hospital with a complaint of cough. Chest imaging revealed diffuse nodular shadows and anterior mediastinal mass. Hypogammaglobulinemia and a decreased B lymphocyte count were found by a laboratory evaluation. The lung nodules markedly regressed after immunoglobulin therapy. The mediastinal mass and remaining nodule were surgically resected and diagnosed as a type AB thymoma and a necrotizing epithelioid granuloma with T lymphocyte-dominant alveolitis, respectively. The overall appearances of these lesions were mostly in line with the spectrum of granulomatous-lymphocytic interstitial lung disease associated with Good's syndrome.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia.

BACKGROUND: Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. METHODS: The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using high-performance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of <5 ng/mL was defined as hypoprolactinemia. RESULTS: Fifty-two of the 66 male patients (79%) and 58 of the 177 female patients (33%) had hypoprolactinemia. There were significant inverse correlations between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.447, P < 0.001) and the active moiety (aripiprazole plus dehydroaripiprazole) (rs = -0.429, P < 0.001) in men. In women, significant inverse correlations were also found between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.273, P < 0.01) and the active moiety (rs = -0.275, P < 0.01). CONCLUSIONS: These findings suggest that lower prolactin levels are, to some extent, associated with higher plasma drug concentrations in male and female patients with schizophrenia treated with aripiprazole.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

BACKGROUND: Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. METHODS: This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. RESULTS: Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). CONCLUSIONS: This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD.

Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine.

INTRODUCTION: To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). METHODS: Seventy-nine Japanese psychiatric patients were treated with MIR for 1-8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. RESULTS: Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight-corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight-corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. DISCUSSION: The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

Total thoracoscopic left ventricular lead implantation for hybrid cardiac resynchronization therapy in pacemaker-mediated cardiomyopathy.

Cardiac resynchronization therapy (CRT) has been increasingly performed in patients having heart failure with dyssynchrony. We report a successful case of total thoracoscopic left ventricular (LV) lead implantation in CRT. A 77-year-old man with marked dyssynchrony of the LV wall motion and a low ejection fraction (EF17%) due to pacemaker-mediated cardiomyopathy was referred to us. CRT was planned, but percutaneous LV lead implantation proved difficult owing to anatomical variations. The LV lead was placed in the post-lateral wall of the LV base using a total thoracoscopic procedure. Preoperative dyspnea and dyssynchrony were clearly improved. In CRT, the LV wall stimulation site is important. The LV lead should be implanted in the latest activation area, which can be detected using speckle tracking echocardiography. Surgical lead implantation can be performed in the ideal area, and this procedure may play a new role as a hybrid CRT.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

The Effects of Fluvoxamine on the Steady-State Plasma Concentrations of Escitalopram and Desmethylescitalopram in Depressed Japanese Patients.

BACKGROUND: The aim of this study was to determine the impact of fluvoxamine, an inhibitor of Cytochrome P450 (CYP) 2C19 (CYP2C19), on the pharmacokinetics of escitalopram, a substrate of CYP2C19. METHODS: Thirteen depressed patients initially received a 20-mg/d dose of escitalopram alone. Subsequently, a 50-mg/d dose of fluvoxamine was administered because of the insufficient efficacy of escitalopram. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using high-performance liquid chromatography before and after fluvoxamine coadministration. The QT and corrected QT (QTc) intervals were measured before and after fluvoxamine coadministration. RESULTS: Fluvoxamine significantly increased the plasma concentrations of escitalopram (72.3 ± 36.9 ng/mL versus 135.2 ± 79.7 ng/mL, P < 0.01) but not those of desmethylescitalopram (21.5 ± 7.0 ng/mL versus 24.9 ± 12.0 ng/mL, no significance [ns]). The ratios of desmethylescitalopram to escitalopram were significantly decreased during fluvoxamine coadministration (0.37 ± 0.21 versus 0.21 ± 0.10, P < 0.01). The CYP2C19 genotype did not fully explain the degree of the change. Fluvoxamine coadministration did not change the QT or QTc intervals. CONCLUSIONS: The results of this study suggest that adjunctive treatment with fluvoxamine increases the concentration of escitalopram. The QTc interval did not change in this condition.

Factors affecting discontinuation of initial treatment with paroxetine in panic disorder and major depressive disorder.

OBJECTIVE: The aims of the present study were to analyze the association between discontinuation of paroxetine (PAX) and the genetic variants of the polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in Japanese patients with panic disorder (PD) and major depressive disorder (MDD). METHODS: The 5-HTTLPR genotype was determined by polymerase chain reaction method. PAX plasma concentration was measured by high-performance liquid chromatography to confirm adherence. RESULTS: When comparing between the PD and MDD patients with the chi-square test and Fisher's exact test, the PD patients had a significant and higher discontinuation rate due to non-adherence than did the MDD patients (13.5% [7/52] versus 0% [0/88], respectively; P<0.001). MDD patients had a significant and higher discontinuation rate due to untraceability than PD patients (12.5% [11/88] versus 1.9% [1/52]; P=0.032). Multilogistic regression revealed a tendency for the long/short and short/short genotypes to affect discontinuation due to adverse effects in PD patients (25.0% versus 6.3%, respectively; P=0.054). CONCLUSION: The results indicate that the 5-HTTLPR genotype might contribute to the discontinuation of initial PAX treatment due to adverse effects in PD patients.

Interaction between paliperidone and carbamazepine.

BACKGROUND: This aim of this study was to determine the impact of carbamazepine on the pharmacokinetics of paliperidone. METHODS: Six schizophrenic patients initially received a 6-12 mg/d dose of paliperidone alone. Subsequently, a 200 mg/d dose of carbamazepine was administered, and the carbamazepine dose was increased to 400 mg/d and then 600 mg/d. Plasma concentrations of paliperidone before and after carbamazepine coadministration were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Carbamazepine significantly reduced the plasma concentration of paliperidone. The plasma concentration of paliperidone at baseline and with coadministration of 200, 400, and 600 mg/d were 45.8 ± 11.7, 26.9 ± 13.7, 17.1 ± 8.2, and 15.9 ± 7.6 ng/mL, respectively. The concentration of paliperidone with carbamazepine coadministration at doses of 200, 400, and 600 mg/d were 55.7% ± 20.7%, 36.1% ± 12.2%, and 33.6% ± 10.4%, respectively, of baseline. This effect occurred even at the carbamazepine dose of 200 mg/d and reached a plateau at doses higher than 400 mg/d. However, carbamazepine coadministration exacerbated the psychotic symptoms in some patients. CONCLUSIONS: The results of the present study suggest that adjunctive treatment with carbamazepine reduces the concentration of paliperidone in a dose-dependent manner, most likely because of the induction of several drug-metabolizing enzymes and several drug transporters.

Downhill oesophageal varices resulting from superior vena cava graft occlusion after resection of a thymoma.

Downhill oesophageal varices (DEV) may occur as a rare complication of superior vena cava (SVC) obstruction. DEV are usually associated with SVC obstruction caused by systemic vasculitis or mediastinal tumours. In this report, we describe a very rare case of DEV resulting from SVC graft occlusion after resection of a thymoma. A 66-year old man with an invasive thymoma was treated by radical resection and bypass grafting from the right brachiocephalic vein to the right atrium. Occlusion of the SVC graft was diagnosed postoperatively; however, the patient could be managed conservatively. Although there had been no significant findings in the oesophagus in previous endoscopic examinations, grade F2 varices were found in the proximal oesophagus in the 19th postoperative month, and DEV caused by SVC graft occlusion was diagnosed. Until now, 2 years since the diagnosis, no apparent symptoms or deterioration of the DEV have been observed. The possible development of DEV should be borne in mind during the follow-up of patients with postoperative SVC graft occlusion.

Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells.

BACKGROUND AIMS: Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. METHODS: 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. RESULTS: Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. CONCLUSIONS: The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.

Overexpression of the miR-34 family suppresses invasive growth of malignant melanoma with the wild-type p53 gene.

Malignant melanoma is the most aggressive neoplasm, with severe metastatic potential. microRNAs represent a class of endogenously expressed, small non-coding RNAs that regulate gene expression. As a consequence, the translation of these mRNAs is inhibited or they are destabilized resulting in downregulation of the encoded protein. The microRNA-34 (miR-34) family, which comprises three processed microRNAs (miR-34a/b/c) was identified as the mediator of tumor suppression by p53. Many reports suggest that the miR-34s contribute to the inhibition of invasion or metastasis in various tumor types. In this study, we evaluated the expression of the miR-34 family in four human melanoma cell lines (A375, G361, C32TG and SK-MEL-24) which have the wild-type p53 gene using real-time reverse transcription PCR. We also examined their generative and invasive characteristics using the cell proliferation assay and the invasion/migration assay, respectively. All four melanoma cell lines showed significant expression of miR-34s - A375: miR-34a 0.6176, miR-34b 0.7625, miR-34c 0.7877; G361: 7.6424, 16.4127, 22.0332; C32TG: 2.1630, 2.1091, 8.4425; SK-MEL-24: 0.3621, 2.5659, 8.5907. The cell doubling times of these cell lines in h:min were as follows: A375 23:23, G361 68:24, C32TG 47:22 and SK-MEL-24 67:03. The in vitro generation times of G361 and SK-MEL-24, which showed increased expression of miR-34c, were significantly shorter than A375 with decreased expression of miR-34c (p=0.0063, ANOVA). Invasion (%) of the four cell lines was as follows: A375 44.0%, G361 22.4%, C32TG 13.8% and SK-MEL-24 45.0%. In vitro invasiveness of G361 and C32TG, which showed increased expression of miR-34a, was significantly suppressed (p= 0.005, ANOVA). These results suggest that overexpression of miR-34a and c suppresses invasive and generative potentials, respectively, in human malignant melanoma.