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In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1(n=11) and ETV6-RUNX1(n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

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The relationship between the risk of endometrial cancer and the use of non-contraceptive estrogens by Japanese postmenopausal women was investigated in a hospital-based case-control study of 1025 women with endometrial cancer and 1267 with other conditions. The overall odds ratio (OR) for estrogen use with or without progestins, compared with never use of any type of estrogens, was 0.917 (95% confidence interval (CI) 0.622-1.353), suggesting that hormone replacement therapy is not a causative agent for endometrial cancer in Japanese women, and that a recent increase in the incidence of endometrial cancer in Japanese women may be related to changes in their life-style. However, although not statistically significant, women who used estrogen without progestin for 12 or more months had an OR of 2.552 (CI 0.231-28.192), while those who used estrogen with progestin for 12 or more months had an OR of 0.425 (CI 0.086-2.113). These results indicate that the addition of a progestin should be considered for reducing the risk of endometrial cancer in Japanese women.

The present study sought to determine the correlation between the vasodilator response of forearm resistance vessels and the circulating levels of nitric oxide (NO) after the administration of oral estrogen for 12 weeks to postmenopausal women. We classified postmenopausal women into two groups: those treated with conjugated equine estrogen (0.625 mg daily) orally for 12 weeks (n = 24) or those who received no treatment (control group, n = 8). Forearm blood flow was measured using strain-gauge plethysmography during hyperemia to evaluate endotheliumdependent vasodilation, and after sublingual nitroglycerin administration to evaluate endothelium-independent vasodilation. Serum levels of nitrite/nitrate (metabolites of NO) and lipid parameters were measured. Basal forearm blood flow, body weight and heart rate were similar in each group. After 12 weeks of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase from 26.9 ± 1.9 to 37.9 ± 3.5 ml/min per 100 ml tissue (p < 0.01), and from 25.2 ± 2.2 to 37.5 ± 3.7 μmol/l (p < 0.05), respectively. No increases were seen in controls. The changes in forearm blood flow after sublingual nitroglycerin were similar before and after 12 weeks of estrogen administration. The increase in maximal forearm blood flow with reactive hyperemia was significantly correlated with the increase in nitrite/nitrate in the group administered estrogen (r = 0.48, p < 0.05). There was no significant correlation between maximal forearm blood flow with reactive hyperemia, nor any change in serum lipids, blood pressure or other parameters. In conclusion, the 12-week administration of oral estrogen increased forearm reactive hyperemia in postmenopausal women, probably via an increase in the production of NO.

This study compares the effects of long-term hormone replacement therapy on the lipid profile of postmenopausal women with or without hypercholesterolemia, with a comparison of 2 different regimens over a 3-year period. A total of 209 women were enrolled in this prospective, nonrandomized trial. They were classified into 2 groups according to baseline serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. The hypercholesterolemic group consisted of 83 subjects with a total cholesterol level of 220 mg/dL or higher and LDL cholesterol 140 mg/dL or higher. The normocholesterolemic group consisted of 126 subjects with normal total and LDL cholesterol levels. Therapy was assigned as follows: 44 subjects in the hypercholesterolemic group and 67 in the normal cholesterol group with a total hysterectomy received conjugated equine estrogen (CEE) 0.625 mg/d, while 39 subjects in the hypercholesterolemic group and 59 in the normal cholesterol group with a physiological menopause received CEE 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d. Fasting blood samples were monitored periodically for 3 years. Nine women withdrew from the study. Hormone replacement therapy had a more favorable effect in the hypercholesterolemic group versus the normal cholesterol group by decreasing total and LDL cholesterol, 7.0% and 16.6%, versus the normal cholesterol group, 0.8% and 3.9%. Serum levels of high-density lipoprotein (HDL) cholesterol were increased in both groups (hypercholesterolemic, 14.4%; normal cholesterol group, 26.5%), with the increase being larger in the normal cholesterol group. These changes were similar with both treatments and were maintained over 3 years. Serum levels of triglyceride were also increased in both groups, with the increase being statistically significant only in the group with normal cholesterol levels at baseline. There were no consistently reported side effects of therapy. The effects of postmenopausal hormone replacement therapy, estrogen with or without progestin, on the lipid profile appear to be related to the subject's baseline lipid values. Thus, such therapy may have a more favorable effect on LDL cholesterol in postmenopausal women with hypercholesterolemia, with the beneficial effect being maintained over 3 years.

By using synchrotron radiation small-angle X-ray scattering (SR-SAXS), we have studied the structural properties of reversed micellar systems depending on hydrocarbon chains of apolar solvents, where we have treated water/bis(2-ethylhexyl)sulfosuccinate (AOT)/n-hexane, n-heptane, n-octane, and isooctane systems. With increasing water/surfactant molar ratio w0 (= [H2O]/[AOT]), we have found that three different phases (oligomeric phase, transient phase, monomeric phase) appear successively in the above systems the same as in the water/AOT/isooctane system. In the present experiments we have found other features of the reversed micellar structure depending on apolar solvents. Thus, the w0 region of the transient phase broadens with increasing the hydrocarbon chain length. The slope of the linear relation between micellar radius and w0 changes systematically depending on the length of linear hydrocarbon chain of apolar solvent, which clearly suggests that the penetration of the solvent molecules into the surfactant layer of the micelle greatly depends on the length of the linear hydrocarbon chain. According to the systematic difference of the above slope from 1.5, where 1.5 is a well-known value obtained from geometrical constraint of micellar packing, we can estimate the penetration limit of apolar solvent with linear hydrocarbon chain to be C9.5; therefore, over C9.5 the penetration of apolar solvent molecules would hardly occur.

BO-1341, a new antipseudomonal semisynthetic cephalosporin, was evaluated for in vitro and in vivo antibacterial activities in comparison with ceftazidime, cefotaxime, and cefoperazone. The in vitro activity of BO-1341 was generally superior or comparable to the activities of the reference antibiotics against clinical isolates of the family Enterobacteriaceae. BO-1341 was highly active against Pseudomonas aeruginosa (MIC for 90% of the strains tested, 1.56 micrograms/ml), Pseudomonas maltophilia (MIC for 50% of the strains tested, 1.56 micrograms/ml), and Acinetobacter calcoaceticus (MIC for 90% of the strains tested, 3.13 micrograms/ml). Furthermore, BO-1341 was highly active against P. aeruginosa isolates resistant to the other antibiotics. Of 199 P. aeruginosa isolates tested, only 2 were resistant to BO-1341. These two strains were also resistant to ceftazidime, cefotaxime, and cefoperazone. Haemophilus influenzae, Branhamella catarrhalis, and nonenteric streptococci were also susceptible to BO-1341, but Staphylococcus aureus, Streptococcus faecalis, and Bacteroides fragilis were not susceptible to the compound. The protective efficacy against experimental infections in mice caused by nine strains of gram-negative bacteria, including P. aeruginosa, reflected the potent in vitro activity.

BO-1236, a new cephalosporin having an N-methyl-5,6-dihydroxyisoindolinium moiety on the 3-methylene of the cephem, showed potent activity against gram-negative organisms, including Pseudomonas aeruginosa. The in vitro activity of BO-1236 was superior or comparable to that of ceftazidime, cefotaxime, and cefoperazone in susceptibility tests with clinical isolates. BO-1236 was significantly more active than ceftazidime against P. aeruginosa strains susceptible or resistant to ceftazidime or gentamicin or both. MBCs were usually close to MICs, both of which were influenced by inoculum size to about the same degree as those of the other beta-lactams. BO-1236 was stable to all types of beta-lactamases except type I oxyiminocephalosporin-hydrolyzing enzyme, by which BO-1236 was slightly hydrolyzed. BO-1236 showed protective activity superior to that of ceftazidime and cefotaxime in experimental infections in mice caused by two strains of P. aeruginosa and showed activity comparable to that of ceftazidime and cefotaxime against other gram-negative bacterial infections.

Objective The aim of the study was to investigate the effects of apolipoprotein E (apo E) phenotype on plasma lipids and bone mass in postmenopausal Japanese women.Methods In 320 subjects aged 40-65 years (mean ± SE, 54.0 ± 0.6), apo E phenotype was determined by isometric electrophoresis. Phenotypic frequencies were 0.3% for E2/2 (n = 1), 8.1% for E3/2 (n = 26), 70.3% for E3/3 (n = 225), 0.6% for E4/2 (n = 2), 19.4% for E4/3 (n = 62) and 1.3% for E4/4 (n = 4). Apo E2/2 and apo E3/2 were classified as E2+ (n = 27); apo E3 homozygotes were placed in another group (E3/3; n - 225), as were apo E4/3 together with apo E4/4 subjects (group E4+; n - 66). Bone density and bone quality were assessed with a newly developed ultrasonic bone densitometer, and plasma lipids were also measured.Results Age, body mass index and years since menopause did not differ significantly between the three groups. The E4+ group had the highest levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, significantly higher than in the E2+ group. Plasma lipoprotein(a) concentrations were significantly higher in the E4+ group than in the other two groups. Ultrasonic parameters of bone density and quality tended to be lower in the E4+ group than in the E2+ group.Conclusions The apo E4 allele was associated with high plasma cholesterol levels and an unfavorable change of bone structure in postmenopausal women.

Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration), as demonstrated by spectrophotometric analysis and microbiological assay. An active enzyme was recovered more rapidly from the inactivated enzyme-monobactam complex derived from the cis form of monobactams than from the complex derived from the trans form of monobactams. This result suggests that the configuration at the 3,4 position on the azetidinone ring of monobactams, together with the chemical structure of the side chains attached to the azetidinone ring, may play an important role in the stability of monobactams to the beta-lactamase of M. morganii.

BO-2727, a new 1-beta-methyl-carbapenem, was active at concentrations of 6.25 micrograms/ml or less against gram-positive and gram-negative bacteria, including some imipenem- and/or meropenem-resistant (MICs, > or = 12.5 micrograms/ml) Pseudomonas aeruginosa strains, against which it proved generally fourfold more active than imipenem and meropenem. BO-2727's antipseudomonal activity and its broad spectrum merit further investigation for clinical use by itself, since it was stable in the presence of renal dehydropeptidase I.

Wear of the valve train area in low–speed operation becomes critical as engines become capable of high–speed and high–power performance. This paper describes the development of a design process to secure for the valve train a constant supply of lubricant film with particular emphasis on maintaining optimum conditions of lubrication in the cam and follower system. With this design process, a valve train made of ordinary materials can be designed to achieve an improved level of scuffing resistance without reduction of maximum load capacity.

The mechanism of the enhanced activity of BO-2727 against imipenem-resistant Pseudomonas aeruginosa was studied by using a set of four isogenic strains derived from beta-lactamase-deficient P. aeruginosa PAO4089 (blaJ blaP). Complementation of the blaJ and blaP mutations conferred greater resistance to biapenem, panipenem, and imipenem than to BO-2727 and meropenem, most notably in the outer membrane protein D2-deficient strain. The higher levels of resistance to biapenem, panipenem, and imipenem can be explained by the slow but significant hydrolysis by beta-lactamase, whereas the reduced levels of resistance to BO-2727 and meropenem would be attributable to their stability in the presence of high levels of beta-lactamase and the fact that they cause only low induction of beta-lactamase. It is also noted that the activity of BO-2727 against the beta-lactamase-deficient strain was less affected by the loss of the D2 porin than was that of meropenem, indicating that BO-2727 in comparison with meropenem can overcome an intrinsic resistance caused by the loss of D2. Moreover, comparative in vitro resistance studies have shown that BO-2727 and meropenem selected fewer resistant cells than other carbapenems. In conclusion, BO-2727 exhibited improved activity against imipenem-resistant P. aeruginosa, probably because of its ability to overcome loss of the D2 porin and beta-lactamase hydrolysis.

Correction to: Leukemia (2016) 30, 1672–1681; doi:10.1038/leu.2016.69 Following the publication of this article, the authors have noted that three genes: FLT3, NRAS and ARID1A (each with mutational frequency of 5%) have been incorrectly labelled in Figure 4a showing the mutational landscape of APL relapse.

Hyperglycemia and its associated Na+/K+pump activity has been implicated in the development of diabetic neuropathy. We recently reported that high glucose in the presence of ouabain induced a progressive increase in the delayed K+current which was suppressed by a blocker of Ca2+‐activated K+channels and blockers of Ca2+channels in rat single myelinated nerve fibers, suggesting an increase of cytosolic free Ca2+concentration ([Ca2+]i). However, the influences of high glucose with ouabain on [Ca2+]iin sensory neurons remain to be elucidated. The present study was undertaken to examine the modulation of depolarization‐induced Ca2+transients by high glucose and ouabain in isolated adult rat dorsal root ganglion (DRG) neurons using the fluorescent Ca2+indicator fura‐2. Bath application of KCl (50 mM) evoked a rapid increase in [Ca2+]ithrough voltage dependent Ca2+channels ([Ca2+]i: 154.2 ± 22.5 nM). This increase was enhanced under high glucose (30 mM D‐glucose) in the presence of ouabain (100 M) ([Ca2+]i: 764.8 ± 210.1 nM). We conclude that a combination of high glucose and decreased Na+/K+pump activity leads to an increase in [Ca2+]iin rat DRG neurons, thereby resulting in nerve dysfunction.

Permanent magnet synchronous (PM) motors can be applied to applications requiring constant power operation, such as traction and spindIe drives by means of flux-weakening control. In a PM motor drive system with flux-weakening control, the motor parameters are used to produce the current vector command. The motor parameters vary because of magnetic saturation and as a result, the control performances are affected by the magnetic saturation. In this paper, the effects of magnetic saturation are examined and the control system considering the magnetic saturation is proposed. The performances of the proposed control system are examined by simulations and the experimental results with respect to the prototype interior permanent magnet synchronous motor.