Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion.

Hypoxia is a driver of cell movement in processes such as development and tumor progression. The cellular response to hypoxia involves a transcriptional program mediated by hypoxia-inducible factors, but translational control has emerged as a significant contributor. In this study, we demonstrate that a cell-cell adhesion molecule, cadherin-22, is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2. We identify new functions of cadherin-22 as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. Silencing eIF4E2 or cadherin-22 significantly impaired MDA-MB-231 breast carcinoma and U87MG glioblastoma cell migration and invasion only in hypoxia, while reintroduction of the respective exogenous gene restored the normal phenotype. Cadherin-22 was evenly distributed throughout spheroids and required for their formation and support of a hypoxic core. Conversely, E-cadherin translation was repressed by hypoxia and only expressed in the oxygenated cells of U87MG spheroids. Furthermore, immunofluorescence on paraffin-embedded human tissue from 40 glioma and 40 invasive ductal breast carcinoma patient specimens revealed that cadherin-22 expression colocalized with areas of hypoxia and significantly correlated with tumor grade and progression-free survival or stage and tumor size, respectively. This study broadens our understanding of tumor progression and metastasis by highlighting cadherin-22 as a potential new target of cancer therapy to disable hypoxic cancer cell motility and adhesion.

[Electrophysiologic and hemodynamic effects of the new bradycardia-inducing substance AQ-A 39]. / Elektrophysiologische und hämodynamische Wirkungen der neuen bradykardisierenden Substanz AQ-A 39.

AQ-A 39 is a new agent with specific bradycardic action on the sinus node. In this study the electrophysiologic and hemodynamic effects of this compound were investigated in 24 patients with various cardiac diseases. The results show: AQ-A 39 causes a significant decrease in enhanced sinus rate. The bradycardic action is more profound at higher sinus rates. In sinus rhythm of normal frequency or, in sinus bradycardia, sinus rate remains unchanged or increases even in the case of sick sinus node syndrome. Conductivity of the AV-node is significantly improved. QT- and QTc-interval increase dose dependently. Other cardiac conduction times and refractory intervals are not significantly changed. In exercise-induced myocardial ischemia increased left ventricular filling pressures are diminished. The extent of this decrease parallels the reduction in heart rate. AQ-A 39 appears to be suitable to reduce inadaequate increases in sinus rate, and seems to be of particular interest in surgical cases or intensive care emergencies as well as in acute ischemic heart disease.

[Hemodynamic effects of the new calcium antagonist nimodipine in normal and increased blood pressure]. / Hämodynamische Wirkungen des neuen Calciumantagonisten Nimodipin bei normalem und erhöhtem Blutdruck.

The new compound nimodipine, a calcium channel-blocking agent, belongs to the dihydropyridine derivatives. In experimental studies it exhibits a preferential vasodilator action on cerebral vascular smooth muscle. We studied the hemodynamic effects of nimodipine in 8 normotensives (5 male, 3 female, mean age 47.8 +/- 3.7 years) and 8 patients (6 male, 2 female, mean age 57.4 +/- 2.6 years) with a systolic blood pressure greater than or equal to 165 mm Hg. After administration of nimodipine in hourly increasing doses of 0.015 mg/kg/h, 0.030 mg/kg/h and 0.045 mg/kg/h by an i.v. infusion, the following parameters were measured continuously: systolic, diastolic and mean arterial pressure (brachial artery), systolic and diastolic pulmonary artery pressure, pulmonary wedge pressure, cardiac and stroke volume index, total vascular resistance, stroke work index, blood flow in the legs by venous occlusion plethysmography and heart rate. Nimodipine provided a significant reduction of systolic, diastolic and mean arterial blood pressures when 0.015 and 0.030 mg/kg/h were infused. The higher dose of 0.045 mg/kg/h did not reduce these values any further. In normotensives cardiac index increased significantly. Hardly any changes in heart rate were observed. Total vascular resistance decreased significantly. Preload remained nearly unchanged. From these results it is concluded that the new calcium antagonist nimodipine provides potent vasodilator effects with a moderate reduction of blood pressure and without significant changes in heart rate.