Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways

Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis. Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of mitochondrial membrane potential [Deltapsim]; cytosolic release of cytochrome c), caspase activation, and apoptosis. Synergistic induction of apoptosis was also observed in other human leukemia cell types (eg, Jurkat, NB4). Coexposure of human leukemia cells to 17-AAG and the PKC inhibitor bisindolylmaleimide (GFX) did not result in enhanced lethality, arguing against the possibility that the PKC inhibitory actions of UCN-01 are responsible for synergistic interactions. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation of Raf-1, MEK1/2, and mitogen-activated protein kinase (MAPK). Coadministration of 17-AAG and UCN-01 did not modify expression of Hsp90, Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further p34cdc2 dephosphorylation and diminished expression of Bcl-2, Mcl-1, and XIAP. In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality. Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon.     

Optimal β-blocker for prevention of atrial fibrillation after on-pump coronary artery bypass graft surgery: Carvedilol versus metoprolol

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia after coronary artery bypass graft (CABG) surgery. It has been shown that prophylactic oral beta-blocker administration reduces the incidence of post-CABG AF. However, the optimal beta-blocker has not been identified. OBJECTIVE: This study sought to determine whether oral carvedilol (with its unique anti-inflammatory and antioxidant properties) is more effective than oral metoprolol for prevention of AF after CABG surgery. METHODS: Between April 2006 and December 2006, 120 patients (63 men, mean age 61 +/- 9.4 years) who were scheduled to undergo their first on-pump CABG were enrolled in this study. The patients were randomized in a prospective 1:1 manner to receive either oral carvedilol (n = 60) or oral metoprolol (n = 60). The end point of the study was the occurrence of the new-onset AF during the first 5 days after CABG. RESULTS: AF occurred in 29 of 120 patients (24.0%). The incidence of postoperative AF was 15.0% (9 of 60) in the carvedilol group and 33% (20 of 60) in the metoprolol group (P = .022). The carvedilol group was treated with mean daily dose of 46 +/- 9 mg and metoprolol group with mean daily dose of 93 +/- 11 mg. There were no differences between the study groups regarding any known preoperative, perioperative, or postoperative characteristics (all values were P >.05). No significant adverse effect was observed in either group. CONCLUSION: This prospective study suggested that oral carvedilol is more effective than oral metoprolol in the prevention of AF after on-pump CABG. It is well tolerated when started before and continued after the surgery. However, further prospective studies are needed to clarify this issue.     

Investigation of Helicobacter pylori infection in beta-thalassaemia major patients with recurrent abdominal pain

BACKGROUND: Recurrent abdominal pain (RAP) affects many children, especially those affected by beta-thalassaemia major. The role of Helicobacter pylori is still unclear in children with RAP. OBJECTIVES: The aim of the present study was the comparison of beta-thalassaemia major patients and normal controls with RAP in H. pylori infection. The factors influencing H. pylori prevalence were also investigated. METHODS: A series of 50 beta-thalassaemia major cases (30 female, 20 male; aged 6-25 years) and 50 age-matched and sex-matched controls, both presenting with RAP, were recruited during a period of 18 months. The study participants were obtained through a multistage random sampling method among those that met Apley's criteria. All the patients and controls had undergone diagnostic oesophagogastroduodenoscopy with biopsy. H. pylori infection was confirmed by two histopathological examinations on an endoscopy sample and a rapid urease test. RESULTS: H. pylori infection in thalassaemic patients was more common than in controls [34/50 (68%) versus 30/50 (60%)], but this higher frequency was not statistically significant. A clear relationship was found between the prevalence of H. pylori and age, duration of transfusion/chelation programmes, pain duration and splenectomy. In contrast, H. pylori did not correlate with abdominal pain characteristics, blood group, serum ferritin level and pathology of the upper gastrointestinal tract. The most frequent endoscopy abnormality was gastritis (72%). Nausea and heartburn were the leading associated symptoms. CONCLUSION: The high prevalence of H. pylori infection suggests that H. pylori should be remembered as a probable cause of RAP in beta-thalassaemia major patients.     

Epithelioid hemangioendothelioma in pleural effusion

Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin with variable morphological features and unpredictable biological behavior. EHE occasionally involves the pleural fluid. However, the cytomorphology of EHE found in pleural fluid has not been well characterized in the literature. Herein we describe a case of EHE, initially presenting as multiple liver lesions plus several small nodular densities at the bases of the lungs followed by bilateral pleural effusions. Diagn. Cytopathol. 2015;43:751–755. © 2015 Wiley Periodicals, Inc.     

The β-cyclodextrin-modified nanosized ZSM-5 zeolite as a carrier for curcumin

Herein, the nanosized ZSM-5 zeolite was synthesized based on a fractional factorial experimental design by a hydrothermal method to study the optimum conditions for the synthesis and formation of the ZSM-5 zeolite by employing different conditions. The samples were synthesized without any organic template, and different conditions, such as the molar composition of the synthesis gel and reaction time, were applied in a wide range. Then, the samples were analysed by X-ray diffraction to investigate the formation of the zeolite ZSM-5, and the results were compared to obtain the optimum conditions for its synthesis. The obtained samples were characterized by SEM, FTIR spectroscopy and TGA. Then, the functionalization of nano zeolite ZSM-5 crystals with β-cyclodextrin (β-CD) was investigated. The zeolite surface was first functionalized with amino groups using an amino alkoxysilane. Then, toluene diisocyanate was reacted with the amino-terminated ZSM-5 zeolite crystals and used for the incorporation of β-CD via its remaining isocyanate groups. After this, a drug delivery system (DDS) was prepared based on the cyclodextrin-modified zeolite with the curcumin anticancer drug, and its formation was studied under experimental conditions. The results of in vitro studies show that this drug delivery system has better characteristics than free curcumin in terms of stability and anti-proliferative and anti-inflammatory effects.

Herein, the nanosized ZSM-5 zeolite was synthesized based on a fractional factorial experimental design by a hydrothermal method to study the optimum conditions for the synthesis and formation of the ZSM-5 zeolite by employing different conditions.