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The contamination of hazardous metal(loid) is one of the serious environmental and human health risks. This study isolated a total of 40 cadmium (Cd)- and arsenic (As)-resistant bacterial isolates from coastal sediments by pour plate technique using tryptic soy agar supplemented with Cd or As (50 mg l) for use as metal(loid) bioremediation agents. Out of 40, 4 isolates, RCd3, RCd6, RAs7, and RAs10, showed a relatively higher growth rate in Cd- or As-supplemented culture media which were selected for further study. The selected isolates showed a high minimum inhibitory concentration (60-400 mg l for Cd and 400-2200 mg l for As), which demonstrated their remarkable Cd and As resistance capabilities. The metal(loid) removal efficiencies (0.032-0.268 μg Cd h mg and 0.0003-0.0172 μg As h mg [wet weight cell]) of selected isolates indicated their greater magnitude in absorbing Cd compared to As from water. Phylogenetic analysis of the 16S rDNA sequences revealed that isolates RCd3, RCd6, RAs7, and RAs10 were closely related to Acinetobacter brisouii, Pseudomonas abietaniphila, Exiguobacterium aestuarii, and Planococcus rifietoensis, respectively. Because of high Cd and As resistance and removal efficiency, the selected isolates can survive in a high metal(loid)-contaminated environment and could be a potential tool for bioremediation of high metal(loid)-contaminated effluents to protect the aquatic environment. [ABSTRACT FROM AUTHOR]

The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to isolate and identify the metal-resistant lactic acid bacteria from sediments of coastal aquaculture habitats for removal of cadmium and lead from ambience. Collected sediment samples were used to isolate the cadmium- and lead-resistant bacterial colonies by spread plate technique using agar media (De Man, Rogosa and Sharpe) supplemented with cadmium or lead at 50 mg/l. Isolates were identified by bacterial colony polymerase chain reaction and sequencing of 16S ribosomal deoxyribonucleic acid. Metal removing probiotic was determined by characterizing the lactic acid yield in culture media, viability in fish intestine, metal-resistant and metal-removal efficiencies. 16S ribosomal deoxyribonucleic acid sequencing data of five (Cd10, Cd11, Pb9, Pb12 and Pb18) and other all isolates clearly showed 99 % similarities to Enterococcus faecium and Bacillus cereus, respectively. The Pb12 exhibited higher lactic acid yield (180 mmol) than that of the remaining E. faecium strains and excellent viability without pathogenicity; therefore, further study was carried out using Pb12 strain. The selected Pb12 strain showed elevated metal resistant (minimum inhibitory concentrations 120 and 800 mg/l for cadmium and lead, respectively) and removal efficiencies [Cadmium 0.0377 mg/h/g and lead 0.0460 mg/h/g of cells (wet weight)]. From the viability and metal removal points of view, it can be concluded that isolated metal-resistant E. faecium Pb12 strains might be used as potential probiotic strains for removing heavy metals from fish intestinal milieu to control the progressive bioaccumulation of heavy metals in the fish. [ABSTRACT FROM AUTHOR]

We propose the enhancement of Λ yield in heavy ion collisions at RHIC and LHC as a novel signal for the existence of diquarks in the strongly coupled quark-gluon plasma produced in these collisions as well as in the Λ . Assuming that stable bound diquarks can exist in the quark-gluon plasma, we argue that the yield of Λ would be increased by two-body collisions between [ ud] diquarks and c quarks, in addition to normal three-body collisions among u, d and c quarks. A quantitative study of this effect based on the coalescence model shows that including the contribution of diquarks to Λ production indeed leads to a substantial enhancement of the Λ / D ratio in heavy ion collisions. [ABSTRACT FROM AUTHOR]

We have fabricated multi-terminal superconductor/normal metal/superconductor junctions comprising superconductor Nb and normal metal Cu. By means of the local and non-local measurements of the junction, we successfully detected the non-existence of a bias current in the Cu wire and the non-local voltage. These results indicate that the current flowing non-locally over the junction is due to the proximity effects and the conversion of the supercurrent and normal current. [ABSTRACT FROM AUTHOR]

Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling. [ABSTRACT FROM AUTHOR]

A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT. [ABSTRACT FROM AUTHOR]

Partially fluorinated metal oxides were studied for manufacturing dichloropentafluoropropanes (CF3CF2CHCl2 and CCl2FCF2CHClF) and controlling the selectivity of their isomers. When activated by elemental fluorine or dichlorodifluoromethane, metal oxides such as TiO2, HfO2, Al2O3, and ZrO2, exhibited catalytic activity in the reaction of dichlorofluoromethane with tetrafluoroethylene. In the case of the TiO2 catalyst, the more fluorine incorporated, the higher the selectivity was for the CCl2FCF2CHClF formation. The fluorine-activated TiO2 catalyst was identified by XRD and XPS as a mixture of TiO2 and partially fluorinated TiO2 including TiOF2. [ABSTRACT FROM AUTHOR]

The report presented here describes a case of spontaneous pneumothorax observed after stereotactic radiotherapy (SRT) for non-small-cell lung cancer (NSCLC). An 84-year-old man with a Stage IIB, T3N0M0 NSCLC in the right upper lobe and a Stage IA NSCLC in the right lower lobe of the lung was treated with SRT for both tumors. He received SRT with a total dose of 60.0 Gy in 10 fractions delivered to the right upper lobe, and 48.0 Gy in 4 fractions delivered to the right lower lobe. Two months after completion of the treatment, he developed spontaneous pneumothorax. He was asymptomatic and recovered with conservative management. Spontaneous pneumothorax has occasionally been reported to occur following thoracic radiotherapy for malignancy. Almost all of the reported cases are patients who had received mantle irradiation for Hodgkin's disease. We have been unable to fi nd any reports of spontaneous pneumothorax after SRT, which has recently been used for treating patients with early-stage NSCLC. Because a case of spontaneous pneumothorax after SRT was observed in our institution, its clinical course is described here along with a discussion of possible causes of spontaneous pneumothorax. [ABSTRACT FROM AUTHOR]

We studied the effect of CMC-544, the calicheamicin-conjugated anti-CD22 monoclonal antibody, used alone and in combination with rituximab, analyzing the quantitative alteration of target molecules, that is, CD20, CD22, CD55 and CD59, in Daudi and Raji cells as well as in cells obtained from patients with B-cell malignancies (BCM). Antibody inducing direct antiproliferative and apoptotic effect, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) were tested separately. In Daudi and Raji cells, the CDC effect of rituximab significantly increased within 12 h following incubation with CMC-544. The levels of CD22 and CD55 were significantly reduced (P<0.001 in both cells) after incubation with CMC-544, but CD20 level remained constant or increased for 12 h. Similar results were obtained in cells from 12 patients with BCM. The antiproliferative and apoptotic effect of CMC-544 were greater than that of rituximab. The ADCC of rituximab was not enhanced by CMC-544. Thus, the combination of CMC-544 and rituximab increased the in vitro cytotoxic effect in BCM cells, and sequential administration for 12 h proceeded by CMC-544 was more effective. The reduction of CD55 and the preservation of CD20 after incubation with CMC-544 support the rationale for the combined use of CMC-544 and rituximab.Leukemia (2009) 23, 1329–1336; doi:10.1038/leu.2009.77; published online 16 April 2009 [ABSTRACT FROM AUTHOR]

Experimental study has been made during cure process of SBR/NR foam rubber. Rubber sample with 30 mm thick, made up by stacking thin rubber sheets in layers, was packed in a metal mold, and peroxide cure was performed by transient heat conduction. Rubber heating time was changed in several steps in order to study the effects of the cure time on the blowing characteristics. Also swelling test was conducted in order to study the relation between the cell structure and the crosslink density. Typical temperature field of one-dimensional, transient heat conduction was observed, and results of the observation studies showed that the cell structure changed depending on both the position from the heating surface and the heating time, and two extreme cell structure, open-cell foam, and closed-cell foam, was clearly observed. Image analyses of the cell structure showed that the porosity distribution increased with the increase of the distance from the heating surface, and the porosity was lower for longer heating time at a same position. Average area of the foam almost took similar results for the result of the porosity, and these various quantities were correlated to the crosslink density. [ABSTRACT FROM AUTHOR]

We have previously shown that two proteins with apparent molecular masses of 91- and 102-kDa (p91 and p102, respectively) in human cytomegalovirus (HCMV)-infected cells are antigenically and structurally related to the major immediate-early (IE) 1 and 2 proteins (IE1p68 and IE2p80, respectively) of HCMV, respectively. In this study, we extended the characterization of p91 and p102 and our results were as follows; (i) Lysine at amino acid position 450 in IE1p68 and at amino acid position 175 or 180 in IE2p80, to which SUMO-1 has been shown to be covalently linked, are required for production of p91 and p102, respectively. (ii) A reversal of cycloheximide (CH) block in the presence of actinomycin D imposed at the time of infection inhibited production of p91, but not p102. (iii) The steady-state levels of p91, but not p102, were remarkably decreased by treatment with proteasome inhibitor MG132, but coincubation with CH inhibited this decrease of p91. (iv) Cell fractionation by differential detergent extraction demonstrated that p91 is preferentially found in detergent-insoluble fraction, although p102 as well as IE1p68 and IE2p80 distributes into all fractions. These results demonstrate that p91 and p102 correspond to SUMO-1-modified IE1p68 and IE2p80, respectively, that the production and degradation of SUMO-1-modified IE1p68 is regulated by mechanisms different from those of SUMO-1-modified IE2p80, and that SUMO-1 modification modulates the intracellular localization of IE1p68, but not IE2p80. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005. [ABSTRACT FROM AUTHOR]

To clarify effective chemotherapeutic regimens against cancer, we examined the effects of glycerol on apoptosis induced by CDDP treatment using cultured human cancer cells (in vitro) and transplanted tumor in mice (in vivo). Human tongue cell carcinoma (SAS) cells transfected with mutated p53 gene (SAS/mp53) showed CDDP-resistance compared with the cells with neo control gene (SAS/neo). When those cultured cells were pre-treated with glycerol, CDDP-induced apoptosis was enhanced by glycerol in SAS/mp53 cells but not in SAS/neo cells. In tumor-transplanted mice, the glycerol treatment to tumors enhanced growth delay induced by CDDP in mp53 tumors transplanted with SAS/mp53 cells, but not in wtp53 tumors transplanted with SAS/neo cells. When transplanted tumors were treated with CDDP alone, the cells positive for active caspase-3, 85kDa PARP and apoptosis were observed by immunohistochemical staining in wtp53 tumors but not in mp53 tumors. When the tumors were treated with CDDP combined with glycerol, positive cells were observed not only in wtp53 tumors but also in mp53 tumors. These results showed that the CDDP-induced growth inhibition of the tumors is p53-dependent and that the enhanced growth delay by glycerol may be due to the increased apoptosis. Glycerol might be available for cancer chemotherapy in patients with m{p53} tumors. [ABSTRACT FROM AUTHOR]

We propose here a novel p53-targeting radio-cancer therapy using p53 C-terminal peptides for patients having mutated p53. Hoechst 33342 staining showed that X-ray irradiation alone efficiently induced apoptotic bodies in wild-type p53 (wtp53) human head and neck cancer cells transfected with a neo control vector (SAS/neo cells), but hardly induced apoptotic bodies in mutation-type p53 (mp53) cells transfected with a vector carrying the mp53 gene (SAS/mp53). In contrast, transfection of p53 C-terminal peptides (amino acid residues 361-382 or 353-374) via liposomes caused a remarkable increase of apoptotic bodies in X-ray-irradiated SAS/mp53 cells, but did not enhance apoptotic bodies in X-ray-irradiated SAS/neo cells. In immunocytochemical analysis, positively stained cells for active type caspase-3 were observed at high frequency after X-ray irradiation in the SAS/mp53 cells pre-treated with p53 C-terminal peptides. In SAS/neo cells, positively stained cells for active type caspase-3 were observed with X-ray irradiation alone. Furthermore, protein extracts from X-ray-irradiated SAS/mp53 cells showed higher DNA-binding activity of p53 to p53 consensus sequence when supplemented in vitro with p53 C-terminal peptides than extracts from non-irradiated SAS/mp53 cells. These results suggest that radiation treatment in the presence of p53 C-terminal peptides is more effective for inducing p53-mediated apoptosis than radiation treatment alone or p53 C-terminal peptide treatment alone, especially in mp53 cancer cells. This novel tool for enhancement of apoptosis induction in mp53 cells might be useful for p53-targeted radio-cancer therapy. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal metho-trexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors. [ABSTRACT FROM AUTHOR]

The SH2 domain-containing inositol 5'-phosphatase (SHIP) is crucial in hematopoietic development. To evaluate the possible tumor suppressor role of the SHIP gene in myeloid leukemogenesis, we examined primary leukemia cells from 30 acute myeloid leukemia (AML) patients, together with eight myeloid leukemia cell lines. A somatic mutation at codon 684, replacing Val with Glu, was detected in one patient, lying within the signature motif 2, which is the phosphatase active site. The results of an in vitro inositol 5'-phosphatase assay revealed that the mutation reduced catalytic activity of SHIP. Leukemia cells with the mutation showed enhanced Akt phosphorylation following IL-3 stimulation. K562 cells transfected with the mutated SHIP-V684E cDNA showed a growth advantage even at lower serum concentrations and resistance to apoptosis induced by serum deprivation and exposure to etoposide. These results suggest a possible role of the mutated SHIP gene in the development of acute leukemia and chemotherapy resistance through the deregulation of the phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3)/Akt signaling pathway. This is the first report of a mutation in the SHIP gene in any given human cancer, and indicates the need for more attention to be paid to this gene with respect to cancer pathogenesis. [ABSTRACT FROM AUTHOR]

The present study examined whether X-ray- and CDDP-sensitivities depend on p53 gene status in human squamous cell carcinoma of the head and neck (SAS cells) showing dominant negative nature of mutant p53 protein. SAS cells were transfected with a vector carrying a mutant p53 gene (SAS/Trp248 cells) or neomycin resistant gene control vector (SAS/neo cells). Sensitivities of the transfected cells to X-ray or CDDP were measured with colony formation assay. The incidence of apoptosis by X-ray or CDDP was analyzed with Hoechst staining or DNA ladder formation assay. The activation of caspase-3 was estimated as an indicator of apoptosis by the detection of fragmentation of caspase-3 or poly (ADP ribose) polymerase (PARP) with Western blot. SAS/Trp248 cells showed X-ray- and CDDP-resistance due to the dominant negative nature of mutant p53, compared with SAS/neo cells. The incidence of DNA ladders and apoptotic bodies increased markedly in SAS/neo cells after X-ray irradiation or CDDP treatment, but increased only slightly in SAS/Trp248 cells. Fragmentation of caspase-3 and PARP was observed in SAS/neo cells, but almost no such fragmentation was observed in SAS/Trp248 cells after X-ray irradiation or CDDP treatment. The present results strongly suggest that the X-ray- and CDDP-sensitivities of human squamous cell carcinomas are p53-dependent, and that the sensitivities are tightly correlated with the induction of apoptosis through caspase-3 activation. The p53-dependent X-ray- or CDDP-sensitivity was supported by results from p53-null human lung cancer H1299 cells which were transfected with wild-type or mutant p53 gene. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi- drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33(+) leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33(+) AML cells from 13 patients, CMA-676 was less effective on CD33(+)CD34(+) than CD33(+)CD34(-) cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33(+)CD34(+) cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33(+) AML with P-gp-related MDR. [ABSTRACT FROM AUTHOR]

Studies arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia. Need for careful electrocardiogram monitoring; Analysis of pertinent topics and relevant issues; Implications on the study of leukemia.

Mutation or inactivation of p53 is known to be present in approximately 50% of human cancers. We propose here a novel strategy for overcoming this problem in mutant p53-targeting cancer therapies. We examined the restoration of radiation-induced p53-dependent apoptosis by a chemical chaperone (glycerol) in human head and neck cancer cells (SAS cells, showing wild-typep53 phenotype). SAS cells transfected with mutant p53 (SAS/mp53) showed radioresistance compared with SAS cells (SAS/neo) transfected with neo vector as a control, but became radiosensitive when pre-treated with glycerol before X-ray irradiation. Apoptosis in the SAS/mp53 cells was induced by X-rays with glycerol pre-treatment, but not without glycerol pre-treatment, whereas apoptosis in the SAS/neo cells was induced in both cases. Gel mobility-shift assays showed that after X-ray irradiation combined with glycerol pre-treatment, mp53 was able to bind to the sequence-specific region upstream of the bax gene regulating apoptosis. These results suggest that glycerol is effective in inducing a conformational change of p53 and restoring normal function to mp53, leading to enhanced radiosensitivity through the induction of apoptosis. This novel tool for enhancement of radiosensitivity in cancer cells bearing mp53 may be useful for p53-targeted radiotherapy. [ABSTRACT FROM AUTHOR]

Interleukin-12 (IL-12) has potent antitumor activities. We examined whether IL-12 enhanced the cytotoxicity of peripheral blood mononuclear cells (PBMNC) and decreased leukemia cells in 30 patients with leukemia or myelodysplastic syndromes (MDS): 12 acute myeloid leukemia (AML) (five in complete remission (CR) and seven in non-CR); six chronic myeloid leukemia (CML); and 12 MDS (three refractory anemia (RA), eight RA with excess of blasts and one chronic myelomonocytic leukemia). PBMNC from patients and five healthy volunteers were cultured at 5 x 10(5)/ml parallel with or without 100 units/ml of IL-12 for 3 days. Cytotoxicity of PBMNC against K562 cells was assessed by flow cytometry. To quantify the amount of leukemia cells, WT1 mRNA was measured by competitive reverse transcription polymerase chain reaction (RT-PCR), since WT1 mRNA is considered as a marker of minimal residual disease (MRD) in leukemia or MDS. The cytotoxicity of non-IL-12-treated PBMNC of 30 patients was 13.4+/-9.3% at the effector to target (E:T) ratio of 20:1, and significantly lower than that of normal subjects (25.7+/-8.4%). The cytotoxicity increased to 30.6+/-17.9% in the IL-12-treated PBMNC. WT1 mRNA in PBMNC of five healthy volunteers was less than 10(3) copies/microg of total RNA. Following the 3-day IL-12 treatment, mean WT1 mRNA of PBMNC was reduced from 10(4.8) to 10(4.2) copies/microg of total RNA in six CML patients, from 10(5.4) to 10(4.8) copies/microg in 12 MDS patients and from 10(5.0) to 10(4.2) copies/microg in five AML patients in CR, but not reduced in five of seven AML in non-CR. These results showed that IL-12 significantly enhanced PBMNC cytotoxicity and decreased the quantity of leukemia cells in PBMNC of most patients with MDS, CML and AML in CR. IL-12 might be of considerable benefit in the elimination of MRD in patients with hematological malignancies. [ABSTRACT FROM AUTHOR]

Lovastatin, a competitive inhibitor of HMG-CoA reductase, reportedly inhibits proliferation and induces apoptosis of tumor cells with MDR-1 coded P-glycoprotein (Pgp) expression. In this study we investigated the sensitivity to lovastatin of eight myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic acid (RA) resistant subline NB4/RA, and their multidrug-resistant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and NB4/RA/MDR. MTT and apoptosis assays revealed that K562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive to lovastatin than their parental cell lines, while NB4/MDR showed the same level of sensitivity as parental NB4 cells, which already were very sensitive to lovastatin. Significant elevation of transcript levels of HMG-CoA reductase was observed by semiquantitative RT-PCR analysis in more than three lovastatin-sensitive MDR sublines, but not in NB4/MDR compared with the parental cell lines. HMG-CoA reductase mRNA levels were up-regulated more than two-fold by the exposure to lovastatin in all of the parental non-Pgp-expressing cell lines. In NB4/MDR, HMG-CoA reductase mRNA level was elevated to a similar extent as in parental NB4, whereas in three other MDR sublines which showed preferential sensitivity to lovastatin, their HMG-CoA reductase mRNA levels were not significantly elevated after 24- and 48-h treatment with lovastatin. These results indicate a connection between drug resistance and regulation of the mevalonate pathway, and further strengthen the clinical possibility that drug resistant leukemias would be susceptible to treatment with lovastatin. [ABSTRACT FROM AUTHOR]

Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA-676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse. However, the mechanism of action of CMA-676 has not been well elucidated. The cytotoxic effect of CMA-676 on HL60, NOMO-1, NB4, NKM-1, K562, Daudi, and the multidrug-resistant sublines, NOMO-1/ADR and NB4/MDR, was investigated by cell cycle distribution and morphology. These studies were done by a video-microscopic system, DNA fragmentation, dye exclusion and 3H-thymidine uptake after analysis of CD33, CD34, P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein and lung-related protein on these cells. A dose-dependent, selective cytotoxic effect of CMA-676 was observed in cell lines that expressed CD33, and was dependent on the amount of CD33 and the proliferative speed of the cells. Sensitive cells were temporally arrested at the G2/M phase before undergoing morphological changes. CMA-676 is not effective on P-gp-expressing multidrug-resistant sublines compared with parental cell lines. MDR modifiers, MS209 and PSC833, restored the cytotoxic effect of CMA-676 in P-gp-expressing sublines. CMA-676 is a promising agent in the treatment of patients with AML that expresses CD33. The combined use of CMA-676 and MDR modifiers may increase the selective cytotoxic effect in multidrug-resistant AML. [ABSTRACT FROM AUTHOR]

Summary. Mouse monoclonal antibody MAB810 is known to recognize the major immediate-early (IE) proteins, 68 kDa IE1 (IE1p68) and 80 kDa IE2 (IE2p80), of human cytomegalovirus (HCMV). Using this antibody we found that two additional proteins with higher molecular weights of approximately 91 (p91) and 102 kDa (p102) are also synthesized in HCMV-infected cells. p91 and p102 were produced in cells stably transfected with plasmid expressing IE1p68 and IE2p80, respectively, and shown to be related with IE1p68 and IE2p80, respectively, in primary amino acid sequence. Taken together, these results indicate that p91 and p102 are expressed from the IE1 and IE2 genes, respectively. [ABSTRACT FROM AUTHOR]

The effect of dibutyryl cyclic AMP (dbcAMP) on interaction of human cytomegalovirus (HCMV) with human central nervous system cell lines was examined. Activation of the major immediate-early (IE) promoter (MIEP) of HCMV by dbcAMP was observed in human neuroblastoma IMR-32 cells, but not in glioma 118MGC and astrocytoma U373-MG cells. The 19 bp repeat element in the enhancer of the MIEP was most likely to be the cis-element that responded to dbcAMP in IMR-32 cells as we expected. In IMR-32 cells activation of the MIEP led to enhanced synthesis of the major IE proteins and infectious HCMV. [ABSTRACT FROM AUTHOR]

In a 27-year-old female with Turner syndrome mosaic, Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) occurred only in the monosomic cells (45, Xc). Extensive cytogenetic studies, including triple-color fluorescence in situ hybridization (FISH), revealed that Ph-positive monosomic cells (45, Xc), Ph-negative monosomic cells and normal diploid cells (46, XX) were present in her bone marrow at diagnosis. After successful interferon therapy, the non-leukemia cells expanded and reconstituted normal hematopoiesis resulting in complete cytogenetic response, following the selective suppression of the monosomic Ph-positive leukemia clone. The ratio of Xc to XX cells in bone marrow cells was significantly increased to that in skin fibroblasts. Moreover, the ratio of Ph-positive cells to Ph-negative cells was found to be significantly different between karyotyping and FISH. Studies of this quite unique case not only confirmed the clonality of CML, effectiveness of interferon-alpha and X chromosome imbalance among different tissues, but also demonstrated a discrepant increase of the BCR/ABL-positive clone in CML. The latter supports the hypothesis that reduced programmed cell death may be the primary mechanism responsible for the expansion of the leukemia clone in CML. Our study verifies the importance of extensive analysis of a neoplastic disease in patients with a constitutional chromosomal abnormality. [ABSTRACT FROM AUTHOR]

Philadelphia (Ph) chromosome or the bcr/abl fusion gene is the hallmark of chronic myeloid leukemia (CML) and serves as a prognostic marker during its treatment. Its detection has been primarily done by karyotype analysis of bone marrow cells. The major limitation of the karyotypic technique is an absolute need for metaphases, often difficult to obtain in an appropriate number in patients under therapy. Fluorescence in situ hybridization (FISH) is a sensitive and quantitative method to detect the bcr/abl fusion gene in cells in both metaphase and interphase. Using M-bcr and abl probes, we performed the interphase FISH in the peripheral blood of 30 healthy volunteers and in 20 hematologically normal bone marrow samples. False-positive cells were detected in 2.7 +/- 0.7% (mean +/- standard deviation) and 2.3 +/- 0.7% among 500 cells, respectively. Then we tested 31 patients with CML at various stages of disease on 50 occasions. Although there was a good correlation between the percentage of FISH-positive cells in the peripheral blood and that in the bone marrow (r = 0.977), between the percentage of FISH-positive cells in the peripheral blood and that of Ph chromosome in the bone marrow (r = 0.841), and between the percentage of FISH-positive cells and that of Ph chromosome in the bone marrow (r = 0.933), the limits of agreement in each group were not small, and thus the peripheral blood FISH test can not be interpreted as the same method with conventional karyotyping. Additionally, we could easily rule out CML in 15 individuals with leukocytosis without performing bone marrow aspiration. The present study indicates that FISH analysis in the peripheral blood is a simple and reliably sensitive test for the detection and quantitative monitoring of the M-bcr/abl fusion gene in CML in routine clinical practice, although this can not entirely replace karyotype analysis of bone marrow cells. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (As2O3) has recently been shown to induce complete remission in acute promyelocytic leukemia (APL). As2O3 reportedly has dose-dependent dual effects on APL cells, triggering apoptosis at relatively high concentrations and inducing differentiation at lower concentrations. However, its effect is still controversial for other AML cells and hematological neoplasms. We studied the in vitro effect of As2O3 on lymphoid lineage cells: lymphoma cell lines, NOL-3, Raji and Daudi, a myeloma cell line, NOP-1, normal peripheral blood lymphocytes (PBL), non-Hodgkin's lymphoma (NHL) cells and chronic lymphocytic leukemia (CLL) cells, and compared it with the effect on APL cell line, NB4, as well as other myeloid cell lines, HL-60 and NKM-1. As2O3 at a concentration of 1 micromol/l markedly inhibited both proliferation and viability of NB4, NOP-1, NOL-3 and NKM-1 cells, but it reduced only viability in normal PBL, CLL cells and NHL cells. As2O3 induced apoptosis and down-regulated bcl-2 expression in NB4, NOP-1 and NKM-1 cells. On the other hand, in HL-60, Raji and Daudi cells, 1 micromol/l As2O3 inhibited only the proliferation weakly, and neither induced apoptosis nor down-regulated bcl-2 expression, but arrested only cell cycle at G1 phase. As2O3 at a low concentration of 0.1 micromol/l had no effect on proliferation and viability of these cells except for NB4. These results showed that As2O3 exerted variable and definite effects on lymphoid cells and indicated that As2O3 might be clinically useful in lymphoid neoplasms such as malignant lymphoma and CLL. [ABSTRACT FROM AUTHOR]

The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in complete remission (CR) were entered into the study. There were 12 males and 18 females; one M0, six M1, 14 M2, three M3, two M4 and four M5 according to FAB classification. The age ranged from 21 to 78 years (median age, 46 years) and the duration of disease-free survival after completion of chemotherapy ranged from 5 to 122 months (median, 35 months). The chemotherapy was performed according to the protocol designed by the Japan Adult Leukemia Study Group (JALSG). PBL subsets were analyzed by flow cytometry with the use of monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD16, CD20, CD45RA, CD56, CD57 and HLA-DR. There was a significant positive relationship between the absolute number of CD4+, CD45RA+ CD4+ cells and the duration of time post-therapy and a significant negative relationship between %CD5+ B, CD56+ cells and the duration of time post-therapy. The appearance of autoantibodies (rheumatoid factor and anti-DNA antibody) tended to increase after 2 years, however, there was no relationship between CD5+ B cells and the frequency of rheumatoid factor. These findings demonstrate that patients in CR have a low number of CD4+ and CD45RA+ CD4+ T cells at an early period after chemotherapy and that each subset recovered to a normal level in 2 years. %CD5+ B and CD56+ cells gradually decreased and returned to their normal level after 4 years. There were high numbers of DR+ T cells and NK cells for a long time, suggesting that activated T cells and NK cells may play a role in the immune surveillance system after chemotherapy. [ABSTRACT FROM AUTHOR]

Leukocytapheresis (LCAP), performed with a leukocyte removal filter, was administered five times, at 1-week intervals, for 5 weeks of intensive therapy and five times, at approximately 1-month intervals, for approximately 5 months of maintenance therapy, to 13 patients with inflammatory bowel disease (IBD) diagnosed as ulcerative colitis (UC) in 8 and Crohn's disease (CD) in 5. Clinical and blood examinations showed no side effects in any of the patients. During the intensive therapy, excellent or moderate clinical response was recognized in 11 of the 13 patients (84.6%), of whom 6 had a dramatic response; the excellent or moderate clinical response continued throughout the maintenance therapy in 8 of the patients (61.5%). Flow cytometry showed that the patients who had improved generally had high values for percentages of HLADR+, HLADR+CD3+, and HLADR+CD8+ cells before the first LCAP, and that these values and the C-reactive protein levels and erythrocyte sedimentation rates had decreased to the normal range by the end of both intensive and maintenance therapy. In the patients who showed poor response, in contrast, all the above values had been at or near normal before the initial LCAP administration. The clinical improvement in the absence of any additional medical treatment suggests that LCAP has the capacity to influence the causal mechanism(s) of IBD and that IBD is strongly associated with the cell-mediated immune response. [ABSTRACT FROM AUTHOR]

Background: The effects of prostaglandin E1 on pulmonary hypertension were assessed after protamine injection at the end of cardiopulmonary bypass during cardiac surgery. Methods: Ten patients scheduled for cardiac surgery presented with pulmonary hypertension (mean pulmonary artery pressure greater than 30 mmHg) after protamine injection and were treated by infusion of 0.02 μg · kg−1 · min−1 prostaglandin E1. Hemodynamic measurements were made on occasions after cardiopulmonary bypass. Prostaglandin E1 decreased pulmonary artery pressure, pulmonary vascular resistance, right ventricular stroke work index and pulmonary vascular resistance/systemic vascular resistance ratio, but did not change blood pressure, systemic vascular resistance, left ventricular stroke work index or cardiac output. Conclusion: Prostaglandin E1 normalized pulmonary hypertension after protamine injection, but did not change arterial blood pressure and cardiac output. [ABSTRACT FROM AUTHOR]

A large-scale, prospective study of tardive dyskinesia (TD) was performed in 11 psychiatric facilities in Japan. A total of 1595 psychiatric patients were enrolled in this study in 1987. The progress of these patients, with the exception of 490 dropouts, has now been followed up to 1988. The prevalence of TD at study entry was 7.6%, the annual incidence rate was 3.7% and the annual remission rate was 28.7%. Newly developed TD patients tended to be older, to have undergone more psychosurgery, and to have had lower neuroleptic doses than the patients who had not developed TD, whereas no specific variable could be detected as a factor associated with remission of TD. The results suggest that the incidence of TD is lower in Japan than that in Europe and North America. [ABSTRACT FROM AUTHOR]

We studied serum thrombopoietin (TPO) levels and circulating numbers of platelet during five courses of myelosuppressive post-remission chemotherapy in three patients with acute leukemia in complete remission. Serum TPO levels were measured by a newly developed and sensitive sandwich enzyme-linked immunosorbent assay. In all courses, serum TPO levels changed reciprocally with the platelet counts. When platelets were transfused into patients near the time of platelet nadir, the TPO levels dropped temporarily, while platelet counts temporarily increased. In addition, platelets obtained after transfusion in a thrombocytopenic patient showed lower binding to biotinylated TPO than donor platelets prior to the transfusion. The finding indicated that the TPO receptors were saturated with endogenous TPO of the patient with a high serum TPO level. These results suggest that the platelet mass directly regulates serum TPO levels by receptor-mediated absorption and is one of the major regulators of serum TPO levels in humans. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Twenty-Seven Cases of Drug-Induced Interstitial Lung Disease Associated With Imatinib Mesylate," that was published in the April 2006 issue.

Leukemia (2003) 17, 648-650. doi:10.1038/sj.leu.2402851 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor commenting on an article about impairment of heart rate variability control during arsenic trioxide treatment for acute promyelocytic leukemia.

We previously reported that intramuscular injections of ubiquitin ligase CBLB inhibitory pentapeptide (Cblin; Asp-Gly-pTyr-Met-Pro) restored lost muscle mass caused by sciatic denervation. Here, we detected Cblin on the basolateral side of Caco-2 cells after being placed on the apical side, and found that cytochalasin D, a tight junction opener, enhanced Cblin transport. Orally administered Cblin was found in rat plasma, indicating that intact Cblin was absorbed in vitro and in vivo. Furthermore, transgenic Cblin peptide-enriched rice (CbR) prevented the denervation-induced loss of muscle mass and the upregulation of muscle atrophy-related ubiquitin ligases in mice. These findings indicated that CbR could serve as an alternative treatment for muscle atrophy., (© 2021. The Author(s).)