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Background: The clinical outcomes of patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors has improved markedly; however, the occurrence of adverse events (AEs) means that elderly patients often cannot be administered the standard dose. Nevertheless, some patients treated with low doses of tyrosine kinase inhibitor have achieved good molecular responses., Patients and Methods: We retrospectively analyzed the efficacy and safety of low-dose dasatinib treatment of elderly CML patients. The study enrolled 21 patients with newly diagnosed, imatinib-resistant, or imatinib-intolerant chronic phase CML. All the patients were aged ≥ 65 years and received dasatinib at a dose of < 100 mg/day. Of these 21 patients, 77% had newly diagnosed CML., Results: Overall, 91% and 72% of patients received a mean dasatinib dose of ≤ 50 mg and ≤ 20 mg, respectively. A molecular response of MR 3 (major molecular response, indicating > 3 log reduction in the number of leukemic cells), MR 4 , and MR 4.5 were achieved in 96%, 77%, and 62% of the patients, respectively. Of the 15 patients who received a mean dose of ≤ 20 mg, 94% achieved a major molecular response, and 74% achieved MR 4 . The most common nonhematologic AE was plural effusion (29%), which was controlled by diuretics and regulating the drug dose., Conclusion: Low-dose (eg, ≤ 20 mg) dasatinib therapy generates an adequate molecular response in most elderly patients with chronic phase CML without causing severe AEs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study investigated the effects of applied nitrogen amounts on specific functional components in mulberry (Morus alba L.) leaves. The relationships between mineral elements and the functional components in mulberry leaves were examined using mulberry trees cultivated in different soil conditions in four cultured fields. Then, the relationships between the nitrogen levels and the leaf functional components were studied by culturing mulberry in plastic pots and experimental fields. In the common cultured fields, total nitrogen was negatively correlated with the chlorogenic acid content (R(2) = -0.48) and positively correlated with the 1-deoxynojirimycin content (R(2) = 0.60). Additionally, differences in nitrogen fertilizer application levels affected each functional component in mulberry leaves. For instance, with increased nitrogen levels, the chlorogenic acid and flavonol contents significantly decreased, but the 1-deoxynojirimycin content significantly increased. Selection of the optimal nitrogen application level is necessary to obtain the desired functional components from mulberry leaves.

Background: The functional components of mulberry leaves have attracted the attention of the health food industry, and increasing their concentrations is an industry goal. This study investigated the effects of solar radiation, which may influence the production of flavonol and 1-deoxynojirimycin (DNJ) functional components in mulberry leaves, by comparing a greenhouse (poor solar radiation) and outdoor (rich solar radiation) setting., Results: The level of flavonol in leaves cultivated in the greenhouse was markedly decreased when compared with those cultivated outdoors. In contrast, the DNJ content in greenhouse-cultivated plants was increased only slightly when compared with those cultivated outdoors. Interestingly, the flavonol content was markedly increased in the upper leaves of mulberry trees that were transferred from a greenhouse to the outdoors compared with those cultivated only in the outdoors., Conclusion: Solar radiation conditions influence the synthesis of flavonol and DNJ, the functional components of mulberry leaves. Under high solar radiation, the flavonol level becomes very high but the DNJ level becomes slightly lower, suggesting that the impact of solar radiation is great on flavonol but small on DNJ synthesis. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Rituximab treatment may cause or exacerbate Kaposi's sarcoma (KS) in patients with human immunodeficiency virus (HIV)-associated multicentric Castleman's disease. Despite the widespread use of rituximab, rituximab-induced KS has not yet been reported in HIV-negative patients with diffuse large B cell lymphoma (DLBCL). We herein report a case of KS that developed after undergoing rituximab-containing chemotherapy in an HIV-negative patient with DLBCL. An 84-year-old man who received rituximab-containing chemotherapy for the treatment of DLBCL developed severe infection, and subsequently KS. Our observations indicate that serious infections under rituximab treatment may trigger KS. KS should therefore be considered when skin tumors appear in lymphoma patients receiving rituximab-containing chemotherapy.

High-molecular-weight kininogen (HMWK) deficiency is a very rare hereditary disorder. We herein report a case of HMWK deficiency with splenic infarction. The HMWK activity of the proband was markedly decreased (0.9%). Direct sequencing of his HMWK gene showed a homozygous "TC" insertion at c523-524 in exon 4. This insertion led to an amino acid substitution, Ser175Ser, resulting in a frameshift mutation and a premature stop codon in amino acid 183. Furthermore, the HMWK activity was also reduced in the patient's three children, who exhibited the heterozygous "TC" insertion at c523-524 in exon 4. This is the first report of this gene alteration in a patient with HMWK deficiency.

The varietal differences in the flavonol glycosides rutin, isoquercitrin, kaempferol 3-(6-rhamnosylglucoside), quercetin 3-(6-malonylglucoside), astragalin, quercetin 3-(6-acetylglucoside), and kaempferol 3-(6-malonylglucoside) contained in mulberry leaves were elucidated. This information was used for breeding mulberry cultivars with a high concentration of functional components. The flavonol content, composition, and proportion in leaves varied widely. 'Kobuchizawa 1' had the highest level of total flavonols (1819 mg/100 g of dry weight), 5 times higher than that of 'Mikurasima 15' (393 mg/100 g of dry weight). Quercetin 3-(6-malonylglucoside) was the most abundant flavonol, although it was not found in all cultivars. Quercetin 3-(6-acetylglucoside) was only found in 'Keguwa'. From the quercetin 3-(6-malonylglucoside) content in crossbred offspring, malonyltransferase, an enzyme involved in quercetin 3-(6-malonylglucoside) synthesis, was acquired according to Mendelian inheritance. An offspring with a higher quercetin 3-(6-malonylglucoside) level than both parents was obtained from the crossing. This suggested that crossbreeding was effective for acquiring cultivars with a higher content of quercetin 3-(6-malonylglucoside).

Background: The epidemiology of human herpesvirus 6 (HHV-6) encephalitis after allogeneic hematopoietic cell transplantation (HCT) and its relationship with HHV-6 reactivation have not been sufficiently characterized., Methods: This prospective, multicenter study of 230 allogeneic HCT recipients investigated the epidemiology of HHV-6 reactivation and HHV-6 encephalitis. Plasma HHV-6 DNA load was prospectively evaluated twice weekly until 70 days after HCT., Results: Cumulative incidence of positive HHV-6 DNA and high-level HHV-6 reactivation (plasma HHV-6 DNA ≥10(4) copies/mL) at day 70 after HCT was 72.2% and 37.0%, respectively. Multivariate analysis identified myeloablative conditioning (hazard ratio [HR], 1.9; P = .004), umbilical cord blood transplantation (UCBT) (HR, 2.0; P = .003), and male sex (HR, 1.6; P = .04) as risk factors for displaying high-level HHV-6 reactivation. HHV-6 encephalitis occurred in 7 patients, and cumulative incidence at day 70 was 3.0%. None of the144 patients without high-level HHV-6 reactivation and 7 of 86 patients (8.1%) with high-level HHV-6 reactivation developed HHV-6 encephalitis (P = .0009). Prevalence of HHV-6 encephalitis was significantly higher among patients receiving UCBT than in patients with other sources (cumulative incidence at day 70, 7.9% vs 1.2%, P = .008). In each of 7 patients with HHV-6 encephalitis, central nervous system (CNS) symptoms developed concomitant with peak plasma HHV-6 DNA (range, 21 656-433 639 copies/mL)., Conclusions: High levels of plasma HHV-6 DNA are associated with higher risk of HHV-6 encephalitis. UCBT is a significant risk factor for HHV-6 encephalitis. HHV-6 encephalitis should be considered if CNS dysfunction develops concomitant to high-level plasma HHV-6 DNA after allogeneic HCT.

Flavonoids are ingested by the general population as anti-oxidant and anti-inflammatory agents. In this study, we investigated the effects of myricitrin, a flavonoid rich in Myrica rubra leaf, upon anti-inflammatory action. Myrica rubra leaf extracts inhibited pro-inflammatory TNFα production in a macrophage cell line, Raw264.7 cells. We observed that the serum IgE levels in the leaf extract-treated DO11.10, a mouse allergy model, were down-regulated. HPLC was performed to demonstrate that M. rubra leaf extracts contain a large amount of myricitrin. We observed an inhibitory effect of HPLC-purified myricitrin on TNFα production in Raw264.7 cells. Thus, myricitrin may be of potential interest in the management of inflammatory conditions.

Job-related traumatic stress experienced by broadcast journalists in Japan was investigated. A questionnaire inquiring about the most traumatic event they faced when covering the news and the Impact of Event Scale-Revised (IES-R) were administered to 270 journalist participants working for Japanese news companies. Of these, 6% met the IES-R criterion for potential posttraumatic stress disorder (PTSD). Moreover, posttraumatic stress reactions at the time of the survey were strongly related to symptoms of stress experienced during the stressful assignment. The early assessment of stress symptoms in journalists that experience traumatic news coverage is important for preventing the development of PTSD symptoms.

A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m(2). On day 4, the leukemic cell number had increased to over 1.0 x 10(9)/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.

Wounding is one of the most effective stress signals to induce ethylene synthesis in persimmon (Diospyros kaki Thunb.). We found that wound-induced ethylene biosynthesis is subjected to negative feedback regulation in mature 'Saijo' persimmon fruit since ethylene production was enhanced by 1-methylcyclopropene (1-MCP) (an inhibitor of ethylene perception) pretreatment, which was approximately 1.8 fold of that in control tissues (without 1-MCP pretreatment). Wound-induced 1-aminocyclopropane-1-carboxylate (ACC) synthase activity and DK-ACS2 gene expression were substantially increased by 1-MCP pretreatment after 12 h, which resulted in much higher ACC content in 1-MCP pretreated tissues than that in a control after 24 h. These results indicated that wound-induced DK-ACS2 gene expression was negatively regulated by ethylene in mature persimmon fruit. However, 1-MCP pretreatment had no effect on DK-ACO1 gene expression, suggesting the independence of wound-induced DK-ACO1 on ethylene. Out of accord with DK-ACO1 gene expression, ACC oxidase activity was enhanced 48 h after wounding in 1-MCP pretreated tissues, reaching a peak 1.5-fold higher than that in control tissues at 60 h.

We cloned and characterized Ty1-copia group retrotransposons in persimmon (Diospyros kaki Thunb.). Genomic DNA or methyl jasmonate (MJA)-treated cDNA were used as templates to amplify the reverse transcriptase region of Ty1-copia group retrotransposons. About 280 bp fragments were amplified and cloned, and 97 clones were sequenced. Forty-nine clones included frameshift or the stop codon, or both. Among 48 clones containing complete reading frames, 42 clones had unique nucleotide sequences. Alignment and phylogenetic analysis of putative amino acid sequences in the 42 clones indicated that these clones (named Tdk; retroTransposon in Diospyros kaki) fell into seven subgroups and six ungrouped sequences, indicating high sequence heterogeneity in Tdk clones. Phylogenetic analysis comparing unrelated plant species shows that some Tdk clones are more closely related to Ty1-copia group retrotransposons in the orders Solanales and Sapindales rather than to other Tdk clones. Southern blot analysis using Tdk2B, Tdk4c, Tdk6Ac, Tdk12K and Tdk13G clones as probes showed that persimmon and its related species, D. lotus, D. lotus var. glabba, D. oleifera, D. rhombifolia and D. virginiana, contained multiple Tdk-like sequences, indicating that homologous elements exist in other Diospyros species.