BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia.

Allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for chronic myeloid leukemia and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia, and the graft-vs-leukemia (GVL) effect can eradicate residual leukemia after allo-SCT. Ph(+) leukemia cells frequently express death-inducing receptors (DR4 and DR5) for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the cytotoxic ligands expressed on cytotoxic T cells and natural killer cells mediating the GVL effect. Here we demonstrate that imatinib specifically downregulated DR4 and DR5 expression in cell lines and clinical samples of Ph(+) leukemia. Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) and short hairpin RNA against bcr-abl also downregulated DR4 and DR5 expression in Ph(+) leukemia cells, and transfection of bcr-abl into a Ph(-) leukemia cell line induced DR4 and DR5 expression, which was abrogated by imatinib treatment. Accordingly, Ph(+) leukemia cells that had been pretreated with imatinib showed resistance to the pro-apoptotic activity of recombinant human soluble TRAIL. These observations demonstrate that BCR-ABL is critically involved in the leukemia-specific expression of DR4 and DR5 and in the susceptibility of Ph(+) leukemia to TRAIL-mediated anti-leukemic activity, providing new insight into the mechanisms of the tumor-specific cytotoxic activities of TRAIL.

Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.

t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.

Point-contact transport properties of strongly correlated electrons on liquid helium.

We present transport measurements of a nondegenerate two-dimensional electron system on the surface of liquid helium at a point constriction. The constriction is formed in a microchannel by a split gate beneath the helium surface. The electrostatic energy of the electron system, which depends in part on the electron density, determines the split-gate voltage threshold of current flow through the constriction. Steplike increases in conductance are observed as the confinement strength is reduced. As the Coulomb interaction between electrons is strong, we attribute this effect to the increase in the number of electrons that can pass simultaneously through the constriction. Close to the threshold, single-electron transport is observed.

Successful tandem (autologous-cord blood) SCT in advanced neuroblastomas with highly amplified MYCN.

Although autologous tandem hematopoietic SCT has improved the prognosis of patients with advanced high-risk neuroblastoma, the results remain unsatisfactory. In an attempt to induce the graft-versus-tumor effect, we performed autologous PBSCT followed by allogeneic cord blood transplantation in three consecutive advanced neuroblastoma cases with marked BM infiltration and high MYCN amplification. Severe acute complications did not occur in any patient and they have maintained disease-free survival for 37-60 months. This strategy appears to be feasible and effective for the treatment of extremely high-risk neuroblastoma cases.

Little impact of donor/recipient major mismatch for neutrophil-specific antigen NA2 on neutrophil recovery after allogeneic SCT.

The Fcgamma receptor IIIb (FcgammaRIIIb), a receptor for the Fcgamma region of IgG, is specifically expressed on neutrophils. It has two allelic polymorphisms, NA1 and NA2, which are highly immunogenic and act as targets in alloimmune or autoimmune neutropenia. Thus, neutrophil antigens (NA) compatibility of donor/recipient pairs might be expected to affect the engraftment of neutrophils after allogeneic SCT (allo-SCT). Here, the impact of NA compatibility of 17 patients and their donors undergoing allo-SCT with a myeloablative regimen was determined. Leukocyte depletion filters were used for all transfusions before and post-SCT; most patients received G-CSF after transplant. Major mismatches for NA1 and NA2 were present in 1 and 7 patient/donor pairs, respectively. These eight patients receiving NA major-mismatched allo-SCT were compared with nine patients who received NA compatible allo-SCT. Engraftment of neutrophils and the incidence of post-engraftment neutropenia were found to be identical in the two groups. Despite the limitations in statistical power because of the small number of patients analyzed, these observations suggest that the major mismatching for NA2 antigen has little impact on the engraftment of neutrophils after myeloablative allo-SCT, at least in patients transfused using leukocyte depletion filters and receiving G-CSF after transplantation.

[Metastatic liver tumor arising from prostate cancer following transurethral resection of the prostate--a report of two cases].

We herein present a report of metastatic liver tumor arising from prostate cancer following transurethral resection of the prostate (TUR) in two patients. The two patients were diagnosed as having moderately differentiated prostate adenocarcinoma, either stage C or B2, and underwent hormonal and/or radiation therapy. TUR was performed due to the patients' complaints of urinary outlet obstruction. Liver metastasis, without evidence of bone or pulmonary metastasis, was then noted 23 and 5 months later in the patients with stage C and B2 prostate cancer, respectively. It is possible that the process of TUR is related to the release of tumor cells from the prostate into the systemic circulation and involved in the development of liver metastasis.

Temporal Transcriptional Pattern of Three Melanin Biosynthesis Genes, PKS1, SCD1, and THR1, in Appressorium-Differentiating and Nondifferentiating Conidia of Colletotrichum lagenarium.

A phytopathogenic fungus, Colletotrichum lagenarium, produces melanized appressoria that display temperature-sensitive differentiation. Conidia incubated in water at 24(deg)C germinated, and germ tubes differentiated into melanized appressoria. On the other hand, conidia incubated in water at 32(deg)C germinated and produced germ tubes that elongated without appressorium differentiation. Conidia in 0.1% yeast extract solution at 32(deg)C germinated and developed into vegetative hyphae. In this study, we investigated the temporal transcriptional pattern of cloned melanin biosynthesis genes, PKS1, SCD1, and THR1, in these differentiating and nondifferentiating conidia. During appressorium differentiation, de novo transcripts of the three melanin biosynthesis genes accumulated 1 to 2 h after the start of conidial incubation at 24(deg)C, and the amount of transcripts began to decrease at 6 h. In conidia germinating in water at 32(deg)C, the transcriptional pattern of the PKS1, SCD1, and THR1 genes was similar to that of these genes in appressorium-forming conidia, although no appressoria were formed. However, in conidia in 0.1% yeast extract solution at 32(deg)C, transcripts of the three melanin biosynthesis genes hardly accumulated.

Precursor of the nuclear-encoded extrinsic 30 kDa protein in photosystem II of Euglena gracilis Z is not a polyprotein.

Polyprotein-type precursors have been reported for the nuclear-encoded proteins such as the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) and the apoproteins of light-harvesting chlorophyll-protein (LHC) in Euglena. We report here that the precursor of the extrinsic 30 kDa protein of photosystem II (PS II) encoded by nuclear DNA is not a polyprotein. The precursor was identified as a 45 kDa protein by immunoprecipitation of in vitro translation products of mRNA and by a pulse-chase experiment. It is probable that the structure of the precursor of the nuclear-encoded protein in Euglena chloroplast is closely related to the feature of assembly, as well as of transport, of the protein in chloroplast.

Characterization of cephalosporin resistance in clinical isolates of Escherichia coli.

The susceptibility of 416 clinical isolates of Escherichia coli to ampicillin, cephaloridine and cefoxitin was determined, and 39 isolates were found to be resistance to 25 micrograms/ml or higher concentrations of cephaloridine. Five of the cephaloridine-resistant strains further exhibited resistance to cefoxitin which is a novel cephamycin antibiotic stable to many types of beta-lactamases. The cephaloridine-resistant strains except the strains resistant to cefoxitin produced a large amount of type I penicillinase mediated by R plasmid, while all the cefoxitin-resistant strains produced a cephalosporinase (2 strains) or both of the cephalosporinase and the type I penicillinase (3 strains). Although the cephalosporinase failed to hydrolyze cefoxitin effectively in vitro, the close relationship between the cephalosporinase production and the cephaloridine and cefoxitin resistances in the E. coli strains was suggested. The conjugal transfer of the cefoxitin resistance to an E. coli strain was unsuccessful.

Frequency analysis of heart rate variability under flight conditions.

The factors causing heart rate variability (HRV) were investigated under various kinds of workloads and flight conditions. Frequency analysis of heart rate, and cross-correlation analysis with blood pressure and respiration, were performed by using the fast Fourier analyser. Consequently, the main frequency of HRV at rest consisted of 0.1 Hz and 0.25-0.3 Hz. These fluctuations disappeared under physical loads, but the value of 0.1 Hz at first increased under moderate mental load and thereafter decreased as the mental load increased. It was suggested that the behavior of the frequency 0.1 Hz under mental load was influenced partly by higher brain centers. For the actual flight, the frequency decreased under takeoff and landing, and remained as at rest during the gunnery and acrobatic training flight. It was concluded that the evaluation of workloads under flight conditions by using the analysis of the factors of HRV was very useful to improve a man-machine interface.

Evaluation method of mental workload under flight conditions.

In order to analyze the relationship between heart rate variability (HRV) and the flight tasks of pilots, HRV of various mental and physical work stresses were investigated. For the physical stress on the treadmill, S.D. of heart rate sequence showed a minimum value at medium stresses and remained there until the maximum stress. However, the centrifuge acceleration test presupposed special physical stresses, and S.D. was almost same as the resting findings. In the tracking tasks, which presupposed maximum interpretative actions, the increase in the mean heart rate (MHR) was small with the S.D. increased a greater amount than for resting results. Consequently, preflight checks and level flight phases presupposed medium interpretative actions and mental stress with reserve capacity. Takeoff and landing phases were considered as both high interpretative action and high emotional stress situations. Acrobatic and gunnery training flight phases were considered physical load, strong interpretative actions, and emotional stress tasks.

Method for determining pilot stress through analysis of voice communication.

Factors inherent in aircraft communication systems hinder customary approaches to voice analysis in the determination of the degree of stress experienced by a pilot during an inflight emergency. By means of a sound spectrogram, the mean vibration space of a voice can be analyzed if the space between the vertical deflections of the vowel sounds is calculated in micrometers. The vibration space shift rate (VSSR) is calculated by comparing the widest vibration space of the voice during the normal phase of the same flight (standard vibration space: SVS) with that encountered during the emergency situation (EVS) by the following formula: VSSR = ((SUS-EVS)/SUS) X 100%. The number of measuring points in each case differs in regard to the length of communication during the emergency. The VSSR can be divided into three phases - normal, urgent, and emergency - each with three grades of 0.5 S.D. apiece.