Product release is rate-limiting for catalytic processing by the Dengue virus protease.

Dengue Virus (DENV) is the most prevalent global arbovirus, yet despite an increasing burden to health care there are currently no therapeutics available to treat infection. A potential target for antiviral drugs is the two-component viral protease NS2B-NS3pro, which is essential for viral replication. Interactions between the two components have been investigated here by probing the effect on the rate of enzyme catalysis of key mutations in a mobile loop within NS2B that is located at the interface of the two components. Steady-state kinetic assays indicated that the mutations greatly affect catalytic turnover. However, single turnover and fluorescence experiments have revealed that the mutations predominantly affect product release rather than substrate binding. Fluorescence analysis also indicated that the addition of substrate triggers a near-irreversible change in the enzyme conformation that activates the catalytic centre. Based on this mechanistic insight, we propose that residues within the mobile loop of NS2B control product release and present a new target for design of potent Dengue NS2B-NS3 protease inhibitors.

Randomised clinical trial: daily pantoprazole magnesium 40 mg vs. esomeprazole 40 mg for gastro-oesophageal reflux disease, assessed by endoscopy and symptoms.

BACKGROUND: Pantoprazole magnesium (pantoprazole-Mg) may display extended inhibition of the proton pump with the potential for improved clinical efficacy in gastro-oesophageal reflux disease (GERD). AIM: To compare the efficacy of pantoprazole-Mg and esomeprazole in GERD. METHODS: Gastro-oesophageal reflux disease (Los Angeles grades A-D) patients were randomised to 4 weeks of treatment with pantoprazole-Mg (n = 290) or esomeprazole (n = 288), both 40 mg once daily, in this multicentre (14 Brazilian sites in 9 cities), double-blind study, with an additional 4 weeks' treatment in nonresponding patients. Severity of oesophagitis (at endoscopy) and GERD-related symptoms (ReQuest-GI) were assessed. The primary end point was the proportion of patients in complete remission (ReQuest-GI score <1.73 plus endoscopic healing) at week 4. RESULTS: Complete remission occurred in 61% of patients in each treatment group at 4 weeks (primary endpoint) and in 81% and 79% of patients in the pantoprazole-Mg and esomeprazole groups at 8 weeks, with no significant differences. Mucosal healing rates were high and not significantly different. At 8 weeks, symptom relief with pantoprazole-Mg was significantly greater than that with esomeprazole (91.6% vs. 86.0%, P = 0.0370) because of continued improvement in symptoms with pantoprazole-Mg from week 4 to week 8 (P = 0.0206). CONCLUSIONS: Pantoprazole-Mg 40 mg was at least as effective as esomeprazole 40 mg for complete remission and the mucosal healing rate was high. Symptom relief with pantoprazole-Mg continued to improve from 4 to 8 weeks and was greater than that with esomeprazole at week 8, suggesting an extended period of treatment effect (ClinicalTrials.gov identifier: NCT01132638).

Real-time monitoring and kinetic parameter estimation of the affinity interaction of jArtinM and rArtinM with peroxidase glycoprotein by the electrogravimetric technique.

ArtinM is a D-mannose binding lectin that has been arousing increasing interest because of its biomedical properties, especially those involving the stimulation of Th1 immune response, which confers protection against intracellular pathogens. The potential pharmaceutical applications of ArtinM have motivated the production of its recombinant form (rArtinM) so that it is important to compare the sugar-binding properties of jArtinM and rArtinM in order to take better advantage of the potential applications of the recombinant lectin. In this work, a biosensor framework based on a Quartz Crystal Microbalance was established with the purpose of making a comparative study of the activity of native and recombinant ArtinM protein. The QCM transducer was strategically functionalized to use a simple model of protein binding kinetics. This approach allowed for the determination of the binding/dissociation kinetics rate and affinity equilibrium constant of both forms of ArtinM with horseradish peroxidase glycoprotein (HRP), a N-glycosylated protein that contains the trimannoside Manα1-3[Manα1-6]Man, which is a known ligand for jArtinM (Jeyaprakash et al., 2004). Monitoring of the real-time binding of rArtinM shows that it was able to bind HRP, leading to an analytical curve similar to that of jArtinM, with statistically equivalent kinetic rates and affinity equilibrium constants for both forms of ArtinM. The lower reactivity of rArtinM with HRP than jArtinM was considered to be due to a difference in the number of Carbohydrate Recognition Domains (CRDs) per molecule of each lectin form rather than to a difference in the energy of binding per CRD of each lectin form.

Efficacy of the Bm86 antigen against immature instars and adults of the dog tick Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae).

The Bm86 antigen has been used to control ticks of the Boophilus genera in integrated programs that also include the use of acaricides. Because of recent phylogenetic studies have lead to the inclusion of all Boophilus species within the Rhipicephalus genera, we aimed to investigate the efficacy of the Bm86 antigen on the biotic potential of Rhipicephalus sanguineus. Domestic dogs were vaccinated with Bm86 and challenged with the three instars of R. sanguineus. Male and female mongrel dogs were divided into two groups of four animals each, comprising non-vaccinated and vaccinated animals. Immunized dogs were given two doses of an experimental formulation containing 50mug of recombinant Bm86, at 21 days interval while the other group was given placebo, consisting of the same preparation without Bm86. Each dog was challenged 21 days after the last dose with 250 larvae, 100 nymphs and 55 adults (25 females and 30 males) released inside feeding chambers (one per instar) glued to their shaved flank. The effect of the vaccination was evaluated by determining biological parameters of ticks including the yield rates of larvae, nymphs and adult females. Adult females engorged weight, egg mass weight, efficiency rate of conversion to eggs (ERCE) and hatchability. In addition, sera were collected from dogs at 0, 21, 36, 45 and 75 days after the vaccination and used for the detection of specific antibodies by ELISA. Collection rates of larvae, nymphs and adult females fed on vaccinated dogs were significantly (p<0.05) reduced by 38%, 29% and 31%, respectively, as compared with non-vaccinated controls. Significant reductions were also observed in weight of engorged females and egg mass, in ERCE, but not in the hatch rate of ticks fed on immunized dogs. ELISA data revealed a marked and significant increase in optical densities of sera from vaccinated animals after the second dose of Bm86. We concluded that the Bm86 antigen used as a vaccine for dogs reduced the viability and biotic potential of the R. sanguineus.

Expression of Umbelopsis ramanniana DGAT2A in seed increases oil in soybean.

Oilseeds are the main source of lipids used in both food and biofuels. The growing demand for vegetable oil has focused research toward increasing the amount of this valuable component in oilseed crops. Globally, soybean (Glycine max) is one of the most important oilseed crops grown, contributing about 30% of the vegetable oil used for food, feed, and industrial applications. Breeding efforts in soy have shown that multiple loci contribute to the final content of oil and protein stored in seeds. Genetically, the levels of these two storage products appear to be inversely correlated with an increase in oil coming at the expense of protein and vice versa. One way to overcome the linkage between oil and protein is to introduce a transgene that can specifically modulate one pathway without disrupting the other. We describe the first, to our knowledge, transgenic soy crop with increased oil that shows no major impact on protein content or yield. This was achieved by expressing a codon-optimized version of a diacylglycerol acyltransferase 2A from the soil fungus Umbelopsis (formerly Mortierella) ramanniana in soybean seed during development, resulting in an absolute increase in oil of 1.5% (by weight) in the mature seed.

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy.

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

Suicidio disimulado como accidente de tráfico. A propósito de un caso / Suicide masquerading as traffic accident: case report

Los motivos que inducen a una persona a enmascarar un suicidio simulando una muerte accidental pueden ser varios. Exponemos un caso en el que la víctima utiliza un accidente de tráfico para disimular un suicidio por arma de fuego y de esta forma conseguir que fuesen abonadas tanto la indemnización del Seguro de Automóviles como los incluidos en un seguro privado contratado poco antes. Sólo a través de una adecuada investigación del lugar de los hechos y de los antecedentes de la víctima junto a la realización del indispensable estudio necrópsico será posible determinar la verdadera etiología médico-legal de las muertes en accidente de tráfico, con especial atención en las que interviene sólo un vehículo con un único ocupante (AU)

There are several reasons that induce somebody tomask a suicide simulating an accidental death. We expose a case in which the victim uses a traffic accident to masquerade a suicide by shotgun. By this way, the authortries to receive the reimbursement of the car’s insurance as well as the money included in a private life insurance contracted just few days before. Only with the careful local death examination and the study of the victim's personal history, plus the essential autopsy, could we manage to understand the real a etiology of deaths in traffic accidents, especially focusing on those cases where there is a single car with a single passenger affected (AU)

The results of a randomized trial looking at 24 weeks vs 48 weeks of treatment with peginterferon alpha-2a (40 kDa) and ribavirin combination therapy in patients with chronic hepatitis C genotype 1.

Peginterferon-alpha plus ribavirin is the most effective therapy for chronic hepatitis C. This study was designed to evaluate the effect of peginterferon alpha-2a (40 kDa) plus ribavirin on sustained virological response (SVR) when administered for 24 vs 48 weeks in genotype 1 naïve patients. One hundred and seventeen patients were enrolled in this controlled trial. Genotype 1 patients were randomized to 24 weeks treatment vs 48 weeks treatment. Genotype non-1 patients received 24 weeks treatment as an observational group. Outcomes were SVR (defined by hepatitis C virus-RNA-negative at week 24 of follow-up) and tolerability across the study period. The end-of-treatment response was 59% for genotype 1 (24 weeks treatment), 80% for genotype 1 (48 weeks treatment) and 92% for genotype non-1 (24 weeks treatment). The end-of-follow-up response was 19% (95% confidence interval (CI): 7.2-36.4) (genotype 1, 24 weeks) and 48% (95% CI: 30.2-66.9; P = 0.0175) (genotype 1, 48 weeks). Among genotype non-1, SVR was 76% (95% CI: 62.3-86.5). There were no unexpected adverse events. Almost half of the genotype 1 patients achieved an SVR after 48 weeks treatment with peginterferon alpha-2a (40 kDa) and low-dose ribavirin and confirmed that they should be treated for 48 weeks. Safety profile was acceptable.

Morphological and functional alterations of the intestine of rats with iron-deficiency anemia.

The present study was designed to assess the intestinal absorption of D-xylose and jejunal morphometry in rats with iron-deficiency anemia. Male Wistar rats were randomly divided into a control group (diet containing 50 mg Fe/kg, N = 12) and an anemic group (diet containing <5 mg Fe/kg, N = 12). The animals were housed in individual metabolic cages and deionized water and diet were provided ad libitum for 6 weeks. Hemoglobin and hematocrit were determined at 0, 2, 4, and 6 weeks. At the end of the study the rats were submitted to a D-xylose absorption test (50 mg/100 g body weight) and sacrificed and a jejunal specimen was obtained for morphometric study. At the end of the study the hemoglobin and hematocrit of the anemic rats (8.7 +/- 0.9 g/dl and 34.1 +/- 2.9%, respectively) were significantly (P < 0.05) lower than those of the controls (13.9 +/- 1.4 g/dl and 47.1 +/- 1.5%, respectively). There was no statistical difference in D-xylose absorption between the anemic (46.5 +/- 7.4%) and control (43.4 +/- 9.0%) groups. The anemic animals presented statistically greater villus height (445.3 +/- 36.8 microm), mucosal thickness (614.3 +/- 56.3 microm) and epithelial surface (5063.0 +/- 658.6 microm) than control (371.8 +/- 34.3, 526.7 +/- 62.3 and 4401.2 +/- 704.4 microm, respectively; P < 0.05). The increase in jejunum villus height, mucosal thickness and epithelial surface in rats with iron-deficiency anemia suggests a compensatory intestinal mechanism to increase intestinal iron absorption.

Morphological and functional alterations of the intestine of rats with iron-deficiency anemia

The present study was designed to assess the intestinal absorption of D-xylose and jejunal morphometry in rats with iron-deficiency anemia. Male Wistar rats were randomly divided into a control group (diet containing 50 mg Fe/kg, N = 12) and an anemic group (diet containing <5 mg Fe/kg, N = 12). The animals were housed in individual metabolic cages and deionized water and diet were provided ad libitum for 6 weeks. Hemoglobin and hematocrit were determined at 0, 2, 4, and 6 weeks. At the end of the study the rats were submitted to a D-xylose absorption test (50 mg/100 g body weight) and sacrificed and a jejunal specimen was obtained for morphometric study. At the end of the study the hemoglobin and hematocrit of the anemic rats (8.7 ± 0.9 g/dl and 34.1 ± 2.9 percent, respectively) were significantly (P < 0.05) lower than those of the controls (13.9 ± 1.4 g/dl and 47.1 ± 1.5 percent, respectively). There was no statistical difference in D-xylose absorption between the anemic (46.5 ± 7.4 percent) and control (43.4 ± 9.0 percent) groups. The anemic animals presented statistically greater villus height (445.3 ± 36.8 µm), mucosal thickness (614.3 ± 56.3 µm) and epithelial surface (5063.0 ± 658.6 µm) than control (371.8 ± 34.3, 526.7 ± 62.3 and 4401.2 ± 704.4 µm, respectively; P < 0.05). The increase in jejunum villus height, mucosal thickness and epithelial surface in rats with iron-deficiency anemia suggests a compensatory intestinal mechanism to increase intestinal iron absorption.

Demographic and anthropometrical analysis and genotype distribution of chronic hepatitis C patients treated in public and private reference centers in Brazil

Hepatitis C virus (HCV) infection is a serious public health problem, since 80 percent to 85 percent of HCV carriers develop a persistent infection that can progress into liver cirrhosis and hepatocarcinoma. Considering that the response of hepatitis C patients to combination therapy with interferon and ribavirin depends on HCV characteristics as well as on host features, we made a retrospective analysis of demographic and anthropometrical data and HCV genotype distribution of chronic hepatitis C patients treated in public and private reference centers in Brazil. The medical records of 4,996 patients were reviewed, 81 percent from public and 19 percent from private institutions. Patients' median age was 46 years, and there was a higher prevalence of male (62 percent) and white patients (80 percent). The analysis of HCV-infecting strains showed a predominance of genotype 1 (64 percent) over genotypes 2 and 3. The patients' mean weight was 70.6 kg, and 65 percent of the patients weighed less than 77kg. Overweight and obesity were observed in 37.8 percent and 13.6 percent of the patients, respectively. Since a body weight of 75 kg or less has been considered an independent factor that significantly increases the odds of achieving a sustained virological response, the Brazilian population seems to have a more favorable body weight profile to achieve a sustained response than the American and European populations. The finding that 65 percent of chronic hepatitis C patients have a body weight of 77 kg or less may have a positive pharmacoeconomic impact on the treatment of genotype 1 HCV patients with weight-based doses of peginterferon.

Demographic and anthropometrical analysis and genotype distribution of chronic hepatitis C patients treated in public and private reference centers in Brazil.

Hepatitis C virus (HCV) infection is a serious public health problem, since 80% to 85% of HCV carriers develop a persistent infection that can progress into liver cirrhosis and hepatocarcinoma. Considering that the response of hepatitis C patients to combination therapy with interferon and ribavirin depends on HCV characteristics as well as on host features, we made a retrospective analysis of demographic and anthropometrical data and HCV genotype distribution of chronic hepatitis C patients treated in public and private reference centers in Brazil. The medical records of 4,996 patients were reviewed, 81% from public and 19% from private institutions. Patients' median age was 46 years, and there was a higher prevalence of male (62%) and white patients (80%). The analysis of HCV-infecting strains showed a predominance of genotype 1 (64%) over genotypes 2 and 3. The patients' mean weight was 70.6 kg, and 65% of the patients weighed less than 77 kg. Overweight and obesity were observed in 37.8% and 13.6% of the patients, respectively. Since a body weight of 75 kg or less has been considered an independent factor that significantly increases the odds of achieving a sustained virological response, the Brazilian population seems to have a more favorable body weight profile to achieve a sustained response than the American and European populations. The finding that 65% of chronic hepatitis C patients have a body weight of 77 kg or less may have a positive pharmacoeconomic impact on the treatment of genotype 1 HCV patients with weight-based doses of peginterferon.

Prevalência de fibromialgia em pacientes infectados com o vírus da hepatite C / Prevalence of fibromyalgia in patients infected by the hepatitis C virus

OBJETIVO: Conhecer a prevalência e as características epidemiológicas de pacientes com fibromialgia e infecção pelo vírus da hepatite C. MÉTODOS: oitenta e quatro pacientes com o vírus da hepatite C foram consecutivamente avaliados em um período de 6 meses. A prevalência da fibromialgia e as características da população foram avaliadas por anamnese, exame físico e revisões de prontuários. RESULTADOS: a síndrome de fibromialgia foi verificada em 12 pacientes (14,2 por cento), com 23 por cento das mulheres entrevistadas apresentando esse diagnóstico. A porcentagem entre homens também foi alta (8 por cento). Outro dado relevante foi a prevalência de alteração do sono encontrada no grupo de pacientes com o vírus da hepatite C, alcançando 50 por cento. Não houve relação entre a prevalência da fibromialgia e o tempo de doença hepática (média de 3,37 anos). Também não foi encontrada diferença no grau de comprometimento hepático (avaliado com ALT e biópsia hepática) entre os grupos com ou sem fibromialgia. CONCLUSÕES: a síndrome de fibromialgia teve grande prevalência neste estudo. A prevalência dessa doença em mulheres infectadas com o vírus da hepatite C foi de aproximadamente 25 por cento, índice elevado em relação à média mundial, mas compatível com a literatura. Embora não faça parte da investigação de rotina, especial atenção deve ser dada, durante a anamnese e exames físicos e laboratoriais, a pacientes com esse quadro. Futuros estudos trarão mais informações sobre essa associação e os mecanismos patogênicos da fibromialgia em pacientes infectados com o vírus da hepatite C.

Area postrema lesion alters the effects of peptide YY on 2-DG-stimulated pancreatic exocrine secretion.

Previously we demonstrated that circulating peptide YY (PYY), which inhibits pancreatic exocrine secretion, binds to specific receptors in the area postrema (AP); therefore we have tested the hypothesis that the removal of the AP (APX) will alter the effects of PYY on pancreatic secretion in awake rats. One-month after AP lesion or sham lesion, rats were implanted with pancreatic, biliary, duodenal, and intravenous catheters. After recovery from the surgery, unanesthetized rats were infused with vehicle or PYY (30 pmol/kg/hr or 100 pmol/kg/hr) under basal or 2-deoxy-D-glucose (2-DG) stimulated (75 mg/kg, intravenous bolus) conditions. PYY at 30 pmol/kg/hr inhibited basal pancreatic fluid secretion in sham-operated rats, but not APX rats. PYY at 100 pmol/kg/hr stimulated basal pancreatic protein secretion in sham-operated rats, and this effect was also lost in APX rats. PYY at 30 and 100 pmol/kg/hr inhibited peak 2-DG stimulated protein secretion to a greater extent in APX rats as compared to sham-operated rats (P < 0.05). Since PYY inhibition of basal pancreatic secretion is AP dependent and inhibition of 2-DG stimulated pancreatic secretion is AP independent, we conclude that the 2-DG pathway of pancreatic secretion differs from the pathway responsible for basal secretion, and that APX potentiates the inhibitory effect of PYY on the 2-DG pathway.

An enteroaggregative Escherichia coli strain of serotype O111:H12 damages and invades cultured T84 cells and human colonic mucosa.

The pathogenic mechanisms of enteroaggregative Escherichia coli (EAEC) are not well defined. We investigated the interaction of EAEC strain 236 (serotype O111:H12) with polarised Caco-2 and T84 human intestinal epithelial cells lines, and with human jejunal and colonic mucosa. Strain 236 adhered to both polarised cell lines and to both intestinal tissue types, but caused severe damage and was invasive only in T84 cells and colonic mucosa. In contrast, prototype EAEC strain 042, which also adhered to the cultured intestinal cell lines, did not adhere to or invade jejunal or colonic tissue. These observations suggest a heterogeneity of virulence properties within the EAEC category of diarrhoea-causing E. coli.

PYY inhibits CCK-stimulated pancreatic secretion through the area postrema in unanesthetized rats.

Peptide YY (PYY) inhibits CCK-8-secretin-stimulated pancreatic secretion in vivo. To investigate whether CCK-8-secretin-stimulated pancreatic secretion is mediated through a vago-vagal pathway and whether PYY inhibits this pathway through the area postrema (AP), chronic pancreatic, biliary, and duodenal catheters were implanted in AP-lesioned (APX) or sham-operated rats. The effects of APX on pancreatic secretion stimulated by bethanechol, pancreatic juice diversion (PJD), or CCK-8-secretin, were tested, with and without background PYY infusion, in unanesthetized rats. APX reduced basal pancreatic secretion by 15-20% (P < 0.01). APX had no effect on bethanechol-stimulated secretion and potentiated protein secretion stimulated by PJD (396 vs. 284%) and exogenous CCK-8-secretin. In sham-operated rats, background PYY potently inhibited CCK-8-secretin-stimulated pancreatic fluid (1.8 vs. 48.2%) and protein secretion (3.7 vs. 45.8%) but potentiated fluid (52.9 vs. 43.1%) and protein (132.9 vs. 68.9%) secretion in APX rats. Our findings demonstrate that PYY inhibits CCK-8-secretin-stimulated pancreatic secretion through an AP-dependent mechanism in sham-operated rats. The AP also contributes to basal pancreatic secretion.

Diversity of surface structures and virulence genetic markers among enteroaggregative Escherichia coli (EAEC) strains with and without the EAEC DNA probe sequence.

The expression of surface structures and the presence of DNA sequences related to putative virulence factors were investigated in 22 enteroaggregative Escherichia coli strains (EAEC). Fimbria was the most frequent (72.7%) structure identified. Only strains hybridising with the EAEC DNA probe carried aggA, but one strain produced a similar but unrelated bundle-like structure. All probe-positive and 62.5% of the probe-negative strains carried the virulence genes tested; aspU and irp2 prevailed among the former strains. The EAEC probe-positive strains were more diverse, and some of these strains, which promoted cell detachment, also carried the hly and pap sequences, thus suggesting they might represent uropathogenic E. coli.

Interferon-gamma sensitizes human myeloid leukemia cells to death receptor-mediated apoptosis by a pleiotropic mechanism.

The role of interferon (IFN)-gamma as a sensitizing agent in apoptosis induced by ligation of death receptors has been evaluated in human myeloid leukemia cells. Incubation of U937 cells with IFN-gamma sensitized these cells to apoptosis induced by tumor necrosis factor-alpha, agonistic CD95 antibody, and tumor necrosis factor-related apoptosis-inducing ligand. Other human myeloid leukemic cells were also sensitized by IFN-gamma to death receptor-mediated apoptosis. Treatment of U937 cells with IFN-gamma up-regulated the expression of caspase-8 and potently synergized with death receptor ligation in the processing of caspase-8 and BID cleavage. Concomitantly, a marked down-regulation of BCL-2 protein was also observed in cells incubated with IFN-gamma. Furthermore, the caspase-dependent generation of a 23-kDa fragment of BCL-2 protein, the release of cytochrome c from mitochondria and the activation of caspase-9 were also enhanced upon death receptor ligation in IFN-gamma-treated cells. Ectopically expressed Bcl-2 protein inhibited IFN-gamma-induced sensitization to apoptosis. In summary, these results indicate that IFN-gamma sensitizes human myeloid leukemic cells to a death receptor-induced, mitochondria-mediated pathway of apoptosis.