High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL ...has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m
) or Id-MTX (0.5 g/m
). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
The active components in cloves are eugenol and isoeugenol. Eugenol has recently become a focus of interest because of its potential role in alleviating and preventing chronic diseases such as ...cancer, inflammatory reactions, and other conditions. The radical-scavenging and anti-inflammatory activities of eugenol have been shown to modulate chronic diseases in vitro and in vivo, but in humans, the therapeutic use of eugenol still remains to be explored. Based on a review of the recent literature, the antioxidant, anti-proliferative, and anti-inflammatory activities of eugenol and its related compounds are discussed in relation to experimentally determined antioxidant activity (stoichiometric factor n and inhibition rate constant) and theoretical parameters phenolic O-H bond dissociation enthalpy (BDE), ionization potential (IP according to Koopman's theorem), and electrophilicity (ω), calculated using a density functional theory method. Dimers of eugenol and its related compounds showed large antioxidant activities and high ω values and also exerted efficient anti-inflammatory activities. Eugenol appears to possess multiple antioxidant activities (dimerization, recycling, and chelating effect) in one molecule, thus having the potential to alleviate and prevent chronic diseases.
Recent studies have suggested that intrauterine undernutrition is closely associated with the pathogenesis of diseases after
birth. Perinatal undernutrition is known to disturb the development of ...reproductive function and delay the onset of puberty
in some species. Using a rat model, we determined the effects of prenatal undernutrition on the development of the hypothalamic
kisspeptin system and evaluated whether the alteration of the kisspeptin system contributes to the delayed onset of puberty
induced by prenatal undernutrition. We also evaluated the effects of prenatal undernutrition on the developmental changes
in serum leptin levels because leptin was a putative positive regulator of the hypothalamic kisspeptin system. We compared
the timing of vaginal opening (VO) and the developmental changes in body weight, hypothalamic Kiss1 mRNA levels, and serum leptin concentrations between offspring with prenatal undernutrition (UN offspring) and normal nutrition
(NN offspring). After birth, the UN offspring showed rapid growth and had caught up to body weight of the NN offspring by
postnatal day 12. After postnatal day 16, the UN offspring showed significantly lower Kiss1 mRNA levels than the NN offspring, despite their significantly higher serum leptin levels (at days 20 and 28). The timing
of VO in the UN offspring was delayed compared with that in the NN offspring, and chronic central injection of kisspeptin
normalized the timing of VO in the UN offspring. These results suggest that decreased hypothalamic kisspeptin action contributes
to the delayed onset of puberty in prenatally undernourished female rats. Increased leptin resistance in the kisspeptin system
might be involved in these alterations.
When discussing treatment options for patients with acute leukemia, it is important to acknowledge the impact of allogeneic hematopoietic cell transplantation (allo-HCT) or chemotherapy on quality of ...life (QOL). We performed a cross-sectional questionnaire study that administered SF-36, FACT-Leukemia and EuroQOL5D to 524 acute leukemia survivors, to compare patient-reported QOL between chemotherapy and allo-HCT, and to elucidate predictors of QOL. Patients who received chemotherapy alone had a better physical QOL than those who received allo-HCT. On the other hand, the allo-HCT group reported a better mental QOL. In the comparison of QOL in the allo-HCT patients according to the presence of GVHD at survey, patients who had GVHD symptoms experienced statistically and clinically significantly worse QOL than those who did not. In the allo-HCT patients without GVHD, the physical QOL was comparable to that in the chemotherapy patients, and they experienced significantly better mental and general QOL than the chemotherapy patients. GVHD and immunosuppressive drugs at survey were strongly associated with worse QOL after allo-HCT. In the chemotherapy group, a shorter time between treatment completion and survey was significantly associated with worse QOL. Further evaluation of QOL by a longitudinal assessment with quantitative and qualitative analyses are warranted.
We resolved the vertical emissivity profiles of H3+ overtone, H3+ hot overtone, and H2 emission lines of the Jovian northern auroras in K band obtained in December 2011 observed by the IR Camera and ...Spectrograph of the Subaru 8.2 m telescope with the adaptive optics system (AO188). The spatial resolution achieved was ~0.2 arcsec, corresponding to ~600 km at Jupiter. We derived the vertical emissivity profiles at three polar regions close to the Jovian limb. The H3+ overtone and H3+ hot overtone lines had similar peak altitudes of 700–900 km and 680–950 km above the 1 bar level, which were 100–300 km and 150–420 km lower, respectively, than the model values. On the contrary, the H2 peak emission altitude was high, 590–720 km above the 1 bar level. It was consistent with the value expected for precipitation of ~1 keV electron, which favors a higher‐altitude emissivity profile. We concluded that the lower peak altitudes of H3+ overtone and hot overtone lines were caused by the nonlocal thermodynamic equilibrium effect stronger than the model assumption. We could reproduce the observational emissivity profiles from the model by including this effect. It has been proposed that neutral H2 and ionized H3+ emissions can have different source altitudes because of their different morphologies and velocities; however, our observed results with a general circulation model show that the peak emission altitudes of H3+ and H2 can be similar even with different velocities.
Key Points
Vertical emissivity profiles of Jovian IR aurora were resolved in K band
H3+ overtone and hot overtone lines had lower peak altitudes than the model
This lower peak was caused by the non‐LTE effect stronger than the model
FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly ...understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly higher than in normal high aldehyde dehydrogenase activity (ALDHhi) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G2/M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21Cip1 and p27Kip1. FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDHhi cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDHhi cells compared with normal ALDHhi cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDHhi cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy.
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must ...continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.
Eugenol (compound
1 in
Fig. 1, 4-allyl-2-methyoxyphenol) and isoeugenol (compound
2 in
Fig. 1, 4-propenyl-2-methoxyphenol), both used as a flavor agent in cosmetic and food products, have both ...prooxidant and antioxidant activities. Their adverse effects such as allergic and inflammatory reaction may be due to their prooxidant activity. To clarify the mechanisms of their cytotoxicity and the factors affecting their antioxidant/prooxidant activities, we investigated the cytotoxicity, ROS production, and cellular glutathione (GSH) levels induced by eugenol and isoeugenol in a human submandibular cell line. The cytotoxicity (MTT method) of eugenol was 1 order of magnitude lower than that of isoeugenol (CC
50: eugenol, 0.395
mM; isoeugenol, 0.0523
mM); and ROS production (CDF staining) was induced significantly by isoeugenol, but not by eugenol. Under treatment with H
2O
2 (100
μM) plus horseradish peroxidase (1
μg/ml) for 30
min or with visible light irradiation for 5
min, eugenol caused biphasic ROS production characterized by enhanced at lower eugenol concentrations (5–10
μM) and decreased at higher concentrations (500
μM). In contrast, isoeugenol enhanced ROS production over a wide range of concentrations (5–500
μM). Isoeugenol at 1000
μM significantly reduced GSH levels compared with eugenol at the same concentration. The high cytotoxicity of isoeugenol may be attributed to its induction of high ROS production and low GSH levels, possibly as a result of benzyl radical formation. In contrast, the cytotoxicity of eugenol is likely to be mediated by ROS-independent mechanisms, possibly involving phenoxyl radicals and/or eugenol quinone methide.
We synthesized various dimer forms of 2-methoxyphenols and 2-tert-butylphenols, as dimers such as curcumin exhibit potent antioxidant and anti-inflammatory activity. We investigated the QSARs between ...the cytotoxicity and independent variables; kinetic parameters (inhibition rate constant (kinh/kp), stoichiometric factor (n)) or DFT-based theoretical parameters (i.e. phenolic O-H bond dissociation enthalpy (BDE), ionization potential according to Koopman's theorem (IP), LUMO, absolute hardness (η), electronegativity (χ) and electrophilicity (ω)) for 2-methoxyphenols and 2- tert- or 2,6-di-tert-butylphenols. The cytotoxicity of these phenols against human tumor cells (HSG, HL60) and/or human gingival fibroblasts (HGF) showed a marked negative linear relationship to kinh/kp, suggesting that the cytotoxicity of phenols may be related to radical reactions. By contrast, a linear relationship between the cytotoxicity and η-term was demonstrated; 2-methoxyphenols showed a negative slope, whereas 2-tert- or 2,6-di-tert-butylphenols showed a positive slope. Also, the cytotoxicity of tert-butylphenols was linearly dependent on the LUMO-term, showing a positive slope. The cytotoxicity of methoxy-substituted monophenols toward both HSG and HGF cells was related to both log P and η- terms. Also, that of X-phenols toward murine L-1210 cells was related to both log P and η or IP-terms, determined from a dataset reported by Zhang et al., 1998. It was concluded that the phenol-induced cytotoxicity was attributable to radical reactions resulting from the terms (kinh/kp, IP, η, and LUMO) in QSAR. The LUMO-dependent cytotoxicity of 2-tert- or 2,6-di-tert-butylphenols may be related to their quinone oxidation products. Experimental and theoretical parameters provide a useful approach for analysis of the cytotoxicity for phenolic compounds.
Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to ...conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438 mm(3) in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48 h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.
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