Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosis.

Evasion of apoptosis, for example, by inhibitor of apoptosis (IAP) proteins, contributes to treatment resistance and poor outcome in acute myeloid leukemia (AML). Here we identify a novel synergistic interaction between the small-molecule second mitochondria-derived activator of caspases (Smac) mimetic BV6, which antagonizes X-linked IAP, cellular IAP (cIAP)1 and cIAP2, and the demethylating agents 5-azacytidine or 5-aza-2'-deoxycytidine (DAC) to induce cell death in AML cells, including apoptosis-resistant cells. Calculation of combination index (CI) confirms that this drug combination is highly synergistic (CI 0.02-0.4). In contrast, BV6 and DAC at equimolar concentrations do not cause synergistic toxicity against normal peripheral blood lymphocytes, pointing to some tumor cell selectivity. Molecular studies reveal that BV6 and DAC cooperate to trigger the activation of caspases, mitochondrial perturbations and DNA fragmentation, consistent with apoptotic cell death. However, the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to protect against BV6/DAC-induced cell death and even significantly increases the percentage of Annexin-V/propidium iodide double-positive cells. Importantly, BV6/DAC-induced cell death in the presence of zVAD.fmk is significantly reduced by pharmacological inhibition of key components of necroptosis signaling, that is, receptor-interacting protein (RIP) 1 using necrostatin-1 or mixed lineage kinase domain-like protein (MLKL) using necrosulfonamide. This indicates a switch from BV6/DAC-induced cell death from apoptosis to necroptosis upon caspase inhibition. Thus, BV6 cooperates with demethylating agents to induce cell death in AML cells and circumvents apoptosis resistance via a switch to necroptosis as an alternative mode of cell death. The identification of a novel synergism of BV6 and demethylating agents has important implications for the development of new treatment strategies for AML.

[Arrhythmogenic right ventricle]. / Arytmogenní pravá komora.

A 26-year-old patient with an irrelevant personal and family-history was treated on account of attacks of relapsing ventricular tachycardia and cardiac failure, mostly dextrolateral. After ruling out other possible causes of the disease--such as embolism of the lungs, ischaemic heart disease, out other possible causes of the disease--such as embolism of the lungs, ischaemic heart disease, Ebstein's anomaly, the diagnosis of an arrhythmogenic right ventricle was established. This disease is suggested by negative T waves in the thoracic leads V1-V3 during sinus rhythm and by the shape of the QRS complex which was the type found in block of the Tawara branch with an axis of + 100 degrees during attacks of ventricular tachycardia. Moreover, ventricular tachycardia of the same type was produced during electrocardiographic examination. On angiographic examination ARVD is suggested by marked trabeculization and impaired kinetics of the outflow tract of the right ventricle. In the prevention of relapses of ventricular tachycardia beta-blockers and Cordarone were successful when used simultaneously with cardiac stimulation type AAI applied on account of a confirmed sinoatrial block.

Iatrogenic clubbing of the fingers.

We report on a 39-year-old female who had been operated on for an atrial septal defect at the age of 14 years. On operation the inferior vena cava was iatrogenically misdirected into the left atrium. The cyanotic patient, in functional group IV of the NYHA classification, with polyglobulia and clubbing of the fingers was successfully reoperated after 25 years.

Cyanoacrylates: an ideal agent for intravascular embolotherapy?

From a large number of various embolic agents introduced in interventional radiology in last two decades it seems that an ideal embolic agent for intravascular embolization has not been found yet. The favourable properties of one of these agents - n-butyl 2-cyanoacrylate are presented by authors. It is concluded that the intravascular embolotherapy with n-butyl 2-cyanoacrylate performed in a strict accordance with the technical demands has proved to be efficient in the management of symptomatic arteriovenous malformations, in the percutaneous transhepatic embolization of gastroesophageal varices and in palliative embolization of renal tumors.

Longterm catheterization of the lingual artery for intraarterial cytostatic therapy.

The authors present a technique of longterm lingual artery catheterization for intraarterial regional chemotherapy. The transtemporal approach enables safe introduction through the external carotid artery. Catheterization technique is presented in 16 patients with the diagnosis of carcinoma baseos oris and carcinoma linguae. Both the lingual arteries were infused in four patients with tumors spreading over the midline. The dislocation of the catheter was found seven times of twenty catheterizations. The following catheter repozition was always successful.