Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.     

Duodenal erosions and ulcers in patients with pancreatobiliary obstruction

The authors compared in a controlled clinical study two groups of patients after a first renal transplantation treated by triple drug immunosuppressive therapy. In a group of 31 patients the triple combination comprised Sandimmune Neoral. In the control group there were 30 patients who received Sandimmune. No differences were found between the two groups as regards the effectiveness of this treatment and the authors did not confirm a lower incidence of rejections described in patients treated with Sandimmune Neoral. They confirmed, however, a lower interindividual variability of Cy-A levels assessed specifically in patients treated with Sandimmune Neoral.     

D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain

Subcellular localization directed by specific A kinase anchoring proteins (AKAPs) is a mechanism for compartmentalization of cAMP-dependent protein kinase (PKA). Using a two-hybrid screen, a novel AKAP was isolated. Because it interacts with both the type I and type II regulatory subunits, it was defined as a dual specific AKAP or D-AKAP1. Here we report the cloning and characterization of another novel cDNA isolated from that screen. This new member of the D-AKAP family, D-AKAP2, also binds both types of regulatory subunits. A message of 5 kb pairs was detected for D-AKAP2 in all embryonic stages and in all adult tissues tested. In brain, skeletal muscle, kidney, and testis, a 10-kb mRNA was identified. In testis, several small mRNAs were observed. Therefore, D-AKAP2 represents a novel family of proteins. cDNA cloning from a mouse testis library identified the full length D-AKAP2. It is composed of 372 amino acids which includes the R binding fragment, residues 333-372, at its C-terminus. Based on coprecipitation assays, the R binding domain interacts with the N-terminal dimerization domain of RIalpha and RIIalpha. A putative RGS domain was identified near the N-terminal region of D-AKAP2. The presence of this domain raises the intriguing possibility that D-AKAP2 may interact with a Galpha protein thus providing a link between the signaling machinery at the plasma membrane and the downstream kinase.     

Epidemiological study of hypertension and its determinants in an urban population of North India

OBJECTIVES: To determine age-specific prevalence of hypertension and blood pressure (BP) levels in relation to diet and lifestyle factors in North Indians. DESIGN AND SETTING: Cross-sectional survey in 20 randomly selected streets in Moradabad, North India. SUBJECTS AND METHODS: A total of 1806 subjects from North India (904 males and 902 females) age range 25-64 years. The survey methods were as follows: dietary diaries for 7 days food intake record; BP measurements; physician administered questionnaire and anthropometric measurements. Diagnosis of hypertension was based on new World Health Organization/International Society of Hypertension (WHO/ISH) criteria. Risk factors were assessed based on WHO guidelines. RESULTS: The prevalence of hypertension according to WHO/ISH criteria was 23.7% and by old WHO criteria 13.3%. In the WHO/ISH hypertensive group, isolated diastolic hypertension was present in 47.3% males and 40.6% females. Males have a slightly higher prevalence than females in the young age group, however, the prevalence rates are comparable in the older age groups. In both sexes, the prevalence rates and BP level increased with older age. Multivariate analysis revealed that age, higher body mass index, central obesity and higher socioeconomic status were independently and strongly associated with hypertension in both sexes. Higher dietary fat and salt intake and lower physical activity were weakly but significantly associated with hypertension. CONCLUSION: Association of higher socioeconmic status, higher body mass index and central obesity in North Indian adults with higher fat intake, lower physical activity and higher prevalence and level of hypertension indicate that these populations may benefit by decreasing the dietary fat intake and increasing physical activity, with an aim to decrease central obesity for decreasing hypertension in North Indians.     

Multibody simulation tool for the calculation of lashing loads on RoRo ships

Approximately 80% of the international transport of goods is carried on by means of ships. A large portion of the transport capacity is represented by Roll-on-Roll-off (RoRo) ships. Especially in Europe this is a relevant potential for the RoRo segment. Consequently, the design and construction of RoRo ships plays an increasing role for German shipyards and their suppliers. In order to make the loading and unloading procedure of trailer economically more competitive, ship owners would like to improve the lashing of trailers on the ship. On the basis of a multibody system formalism, a software tool has been developed which allows for an optimization of the loading of trailers on RoRo ships. Commemorative Contribution.     

Kinetics of hydantoin formation

The reaction of lignite in a slagging gasifier produces reactants which in turn form 5,5-dimethylhydantoin (DMH) as a major constituent in the condensate water. Variations in plant operating conditions made it impossible to accurately study the kinetics of formation of DMH in the actual gasifier water, and thus a model system was chosen. The reaction of acetone cyanohydrin in the presence of excess ammonium carbonate at concentrations approaching those obtained in the condensate water were studied at 50,70, and 90 °C. Secondorder kinetics were obeyed, and the pseudo second-order rate constants at the respective temperatures were 1.86, 3.6, and 4.62 dm³ mol^{? 1} h^{? 1}. Independent variation of the concentration of either acetone, cyanide, ammonia or carbonate gave results consistent with the interpretation that the formation of DMH is first order in all reactants: rate of formation of DMH = k[acetone][HCN][NH₃][CO₂]. The pseudo second-order rate constant is a complex rate constant including several rapid equilibria. A mechanism consistent with the kinetic data is presented.