The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias.

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.

[Successful implantation of a metal coronary angioplasty stent for bronchomalacia of the right tracheal bronchus associated with right isomerism complex in an early infant].

One-month-old boy had severe emphysema of the right upper lobe due to the stenotic tracheal bronchus compressed between the distorted right patent ductus arteriosus (PDA) and the right aortic arch associated with right isomerism complex. He underwent a left modified Blalock-Taussig shunt and a division of the PDA on cardiopulmonary bypass. Extracorporeal lung support (ECLS) was introduced because of severe hypoxemia caused by remaining bronchomalacia of the tracheal bronchus. On postoperative day 3, a metal coronary angioplasty stent was implanted at the stenotic lesion under fluoroscopic and bronchoscopic guidance. He was successfully weaned from ECLS and then respirator after the implantation. This simple stenting procedure might be an effective alternate in the treatment of bronchomalacia or bronchial stenosis in early infancy.

[Oral sildenafil citrate as an effective alternate in the treatment of postoperative pulmonary hypertensive crisis after congenital heart surgery].

A five-month-old girl of Down syndrome underwent a corrective surgery for complete atrioventricular septal defect. Her postoperative course was complicated with pulmonary hypertensive (PH) crises despite nitroglycerin (NTG) infusion and inhaled nitric oxide (NO). Sildenafil citrate, a phosphodiesterase 5 inhibitor, was administered through a nasogastric tube at a starting dose of 0.3 mg/kg by stepwise increment to the maximum dose of 2 mg/kg 4 hourly. Sildenafil citrate dramatically lowered pulmonary arterial pressure and the patient was weaned from NTG and NO without PH crisis. There was no side effect after sildenafil citrate administration. Oral sildenafil citrate is a safe and potent adjunct to the existing therapies for postoperative PH in infants after open heart surgery.

Comparison of the right and left ventricle as a systemic ventricle during exercise in patients with congenital heart disease.

BACKGROUND: Few studies have investigated the clinical advantages of surgical correction with the morphologic left ventricle (MLV) instead of the morphologic right ventricle as a systemic ventricle (SV) in patients with congenital heart disease. METHODS: Twenty-four healthy control subjects (group A1), 6 patients with isolated congenitally corrected transposition of the great arteries (TGA) (group A2), 16 patients with TGA who had undergone an arterial switch operation (group B1), 18 patients with TGA who had undergone a venous switch operation (group B2), 9 patients with atrioventricular and ventriculoarterial discordance who had undergone a double switch operation (group C1), and 6 patients with atrioventricular and ventriculoarterial discordance who had undergone a conventional external conduit operation from the MLV to the pulmonary artery (group C2), performed treadmill exercise testing. Their heart rate (HR), oxygen uptake (VO2), and oxygen pulse (O2 pulse), which reflects individual stroke volume, were measured, and contractile function was assessed by echocardiography. RESULTS: The peak HR for the patients after a definitive operation were significantly lower than that in group A1 and was correlated with peak VO2 (r =.67, P <.0001). The peak VO2 and peak O2 pulse for the groups A2 and B2 were significantly lower than those for the groups A1 and B1, respectively. The peak O2 pulse data were strongly correlated with those of peak VO 2 (r = 0.91, P <.0001). The left ventricular ejection fraction was significantly lower in groups B1 and C1 than in group A1 and was correlated with peak VO 2 (r =.50, P <.01). No significant differences in VO2, HR, and O 2 pulse at peak exercise were observed between groups C1 and C2. CONCLUSIONS: Chronotropic incompetence and an impaired response of the stroke volume of the MRV during exercise are partly responsible for the reduced exercise capacity in groups A2 and B2 compared with groups with the MLV as an SV, and the SV function at rest is also related to exercise capacity. Superiority of the double-switch operation compared with the conventional conduit operation was not observed. A longer-term follow-up is necessary before the advantages of these 2 operations can be compared.

Cardiorespiratory response during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation and in patients with congestive heart failure.

To clarify the different cardiorespiratory response to exercise in patients with congenital heart disease and patients with chronic congestive heart failure, we investigated the effect of a progressive exercise test in 30 patients aged 10 to 24 years, including 9 patients with cyanotic congenital heart disease (group A), 13 patients who had undergone a Fontan operation (group B), and 8 patients with reduced left ventricular function (group C), and 18 healthy controls (group D). There was no difference in peak oxygen uptake among patient groups and all group A, B, and C values were lower than those in group D (P<0.001). Although peak heart rate was lower in patient groups than in group D, heart rate at a given exercise intensity was highest in group C. The oxygen pulse (oxygen uptake divided by heart rate=stroke volume x arterial venous oxygen difference), as an indicator of stroke volume, was lower in patients groups, especially in group C, than in group D. There was no difference in tidal volume between groups A and D, but the respiratory rates at any given exercise intensity were higher in group A than in the other patient groups, thus minute ventilation and the ventilatory equivalent were highest in group A. The increased respiratory rate and low tidal volume in group C resulted in rapid and shallow respiration. There was no difference in exertional symptoms at peak exercise among the groups. In addition to impaired responses of stroke volume during exercise in patients with reduced exercise capacity, there was little limitation of increase in ventilation in group B and excessive ventilation in group A. The present results suggest that relationship between ventilatory and cardiac responses during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation is different from the relationship in patients with chronic congestive heart failure; however, these pathological differences did not influence exertional symptoms.