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L-Asparaginase (ASNase) has proved its use in medical and food industries. Sequence-based screening showed the thermophilic Streptomyces strain Streptomyces thermoluteus subsp. fuscus NBRC 14270 (14270 ASNase) to positive against predicted ASNase primary sequences. The 14270 ASNase gene and four L-asparaginase genes from Streptomyces coelicolor, Streptomyces avermitilis, and Streptomyces griseus (SGR ASNase) were expressed in Streptomyces lividans using a hyperexpression vector: pTONA5a. Among those genes, only 14270 ASNase and SGR ASNase were successful for overexpression and detected in culture supernatants without an artificial signal peptide. Comparison of the two Streptomyces enzymes described above demonstrated that 14270 ASNase was superior to SGR ASNase in terms of optimum temperature, thermal stability, and pH stability.

X-prolyl dipeptidyl aminopeptidases (X-PDAPs) are useful in various food industries. In this study, we performed sequence-based screening to obtain a stable X-PDAP enzyme from thermophilic Streptomyces strains. We found three genes that encoded X-PDAP from Streptomyces thermoluteus subsp. fuscus NBRC 14270 (14270 X-PDAP), Streptomyces thermocyaneoviolaceus NBRC 14271 (14271 X-PDAP), and Streptomyces thermocoerulescens NBRC 14273, which were subsequently cloned and sequenced. The deduced amino acid sequences of these genes showed high similarity, with ~80% identity with each other. The isolated X-PDAPs and an X-PDAP from Streptomyces coelicolor were expressed in Streptomyces lividans using a hyperexpression vector: pTONA5a . Among these genes, only 14270 and 14271 X-PDAPs caused overexpression and extracellular production without artificial signal peptides. We also characterized the biochemical properties of purified 14271 X-PDAP. In addition, we found that, in peptide synthesis via an aminolysis reaction, this enzyme recognized d -amino acid derivatives as acyl acceptors, similar to l -amino acid derivatives.

(La0.7Sr0.3)MnO3 thin films were deposited on SiO2/Si substrates by a metal-organic decomposition (MOD) method, and then Pb(Zr0.52Ti0.48)O3 (PZT) thin films were grown on (La0.7Sr0.3)MnO3-coated SiO2/Si substrates by a sol-gel method. The effects of annealing temperature on the crystalline phases, microstructures and electrical properties of the PZT films were investigated. X-ray diffraction analysis results indicated that the PZT films with a perovskite single phase could be obtained by annealing at 650°C. The dielectric constant and the remnant polarization of the PZT films increased with increasing annealing temperature. The remnant polarization and the coercive field of the films annealed at 650°C were 18.3 μC/cm2 and 35.5 kV/cm, respectively, whereas the dielectric constant and loss value measured at 1 kHz were approximately 1100 and 0.81, respectively.

l -Asparaginase (ASNase) has proved its use in medical and food industries. Sequence-based screening showed the thermophilic Streptomyces strain Streptomyces thermoluteus subsp. fuscus NBRC 14270 (14270 ASNase) to positive against predicted ASNase primary sequences. The 14270 ASNase gene and four l -asparaginase genes from Streptomyces coelicolor , Streptomyces avermitilis , and Streptomyces griseus (SGR ASNase) were expressed in Streptomyces lividans using a hyperexpression vector: pTONA5a . Among those genes, only 14270 ASNase and SGR ASNase were successful for overexpression and detected in culture supernatants without an artificial signal peptide. Comparison of the two Streptomyces enzymes described above demonstrated that 14270 ASNase was superior to SGR ASNase in terms of optimum temperature, thermal stability, and pH stability.

Background Dasatinib, which is used to treat treating chronic myeloid leukemia, induces increases in blood lymphocytes during the treatment. In addition, neutrophil–lymphocyte count ratio (NLR) is associated with the related to development of chronic kidney disease (CKD). However, it has not been reported whether development of CKD during long-term dasatinib treatment is related to lymphocyte count or NLR. This study aimed to reveal the relationship between CKD and lymphocyte count or NLR during long-term dasatinib treatment. Methods A retrospective study was conducted in patients treated with dasatinib for 6 months or longer. Risk factors for CKD development were explored using multivariate analysis. Changes in maximal lymphocyte count and NLR over time were examined separately. Results A total of 33 patients in CKD group ( n  = 8) and No CKD group ( n  = 25) who received dasatinib were enrolled. In univariate analysis, significant differences between the groups were observed in maximal lymphocyte count, lymphocytosis, age, and estimated glomerular filtration rate at baseline. As the factor independently associated with the development of CKD, maximal lymphocyte count (odds ratio 0.999, 95% confidence interval: 0.999–1.000, p  = 0.033) was identified. In this analysis, age had borderline significance (odds ratio 1.073, 95% CI: 0.999–1.153, p  = 0.054)]. After 6 months of dasatinib therapy, lymphocyte count was significantly lower in CKD group [median (range), 2184 (878‒3444)/μL] than in the No CKD group [3501 (966‒7888)/μL] ( p  = 0.020). However, no significant difference in lymphocyte count was observed between the groups at the last follow-up. During the study period, the median NLR in the No CKD group fluctuated between 1.11 and 1.42, and median NLR in CKD group was increased from 1.13 to 2.24 between after 6 months of dasatinib therapy and the last follow-up. Conclusions The development of CKD during dasatinib therapy was associated with lower maximal lymphocyte counts. In contrast, the higher levels of lymphocytes induced during dasatinib treatment may prevent CKD progression.

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m2) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)

Background Erythrocyte transfusion is an indispensable component of supportive care after hematopoietic stem cell transplantation (HSCT). However, HSCT recipients are susceptible to the development of acute kidney injury (AKI) with multifactorial causes. We report a case of a rapid elevation in serum creatinine associated with deferoxamine after cord blood transplantation (CBT). Case presentation A 36-year-old Japanese male diagnosed with relapsed Philadelphia-positive acute lymphoblastic leukemia received CBT. At day 88 post-CBT, multidrug-resistant Pseudomonas aeruginosa (MDRP) was isolated from urine culture. Subsequently, colistin 200 mg/day was administered parenterally for treatment of epididymitis from day 91 to 117 post-CBT. Despite concomitant administration of potential nephrotoxic agents such as piperacillin-tazobactam, acyclovir, and liposomal amphotericin B, no development of AKI was observed during this period. At day 127 post-CBT, MDRP was detected in blood and urine cultures, and colistin 200 mg/day was re-started parenterally. Due to extremely higher ferritin level, deferoxamine was administered intravenously at day 133 post-CBT. While serum creatinine was 1.03 mg/dL before starting deferoxamine, the level increased to 1.36 mg/dL one day after commencing deferoxamine (day 134 post-CBT), and further increased to 2.11 mg/dL at day 141. Even though colistin was discontinued at day 141 post-CBT, serum creatinine continued to increase. Deferoxamine was withdrawn at day 145 post-CBT, when serum creatinine peaked at 2.70 mg/dL. In addition, no cylinduria is observed during the period of development of AKI. In adverse drug reaction (ADR) assessment using Naranjo probability score, the scores of 3 in deferoxamine and 2 in colistin, respectively, indicated “possible” ADR. However, while colistin-associated AKI manifested early onset, recovery time within 2 weeks after discontinuation and development of cylinduria, this case was discordant with the properties. Furthermore, in the literature review, development of AKI within 1 day, including sudden increase in serum creatinine or abrupt reduction in urine volume, was reported in 3 identified cases. Conclusions We considered the rapid creatinine elevation to be the result of deferoxamine rather than ADR caused by colistin. Therefore, careful monitoring of kidney function is required in recipients of HSCT treated with deferoxamine.

Among patients with PS 2–3 at study enrollment (10 patients each in both arms), the long-term PFS in Arm A also tended to be better compared with that in Arm B. As our eligibility criteria permitted the enrollment of patients with PS 3 only resulting from osteolytic lesions (six patients in Arm A and eight patients in Arm B), rapid responses to treatment and improvement of patients' condition could have resulted in better PFS in Arm A. In JCOG1105, although a higher median cumulative dose of melphalan was administered in Arm A (324 mg/m2) compared with in Arm B (252 mg/m2), a lower incidence of second primary malignancies was observed in Arm A (one patient) compared with in Arm B (five patients; Table 1). TABLE 1 Second primary malignancies Arm Second primary malignancy Onset of second primary malignancy after protocol treatment Subsequent treatment Arm A Early gastric cancer 214 days None Arm B Esophageal cancer 31 months Lenalidomide/dexamethasone Acute myeloid leukemia 26 months Lenalidomide/dexamethasone Cutaneous squamous cell carcinoma 106 days None Prostate cancer 23 months Lenalidomide/dexamethasone Intramucosal gastric cancer 35 months Lenalidomide/dexamethasone In summary, the final analysis of JCOG1105 demonstrated that twice-weekly dosing of bortezomib in the first cycle along with higher dose of melphalan and higher cumulative dose of both bortezomib and melphalan (Arm A) confers sustained PFS benefit with no new AE-related concerns. Abbreviations AE adverse event CI confidence interval CR complete response HR hazard ratio JCOG Japan Clinical Oncology Group MPB melphalan, prednisolone, bortezomib MRD minimal residual disease OS overall survival PFS progression-free survival PS performance status TI-NDMM transplant-ineligible newly diagnosed multiple myeloma

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.