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Non-Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose-escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose-limiting toxicities (DLT), maximum-tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment-emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3-mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Repeat-induced gene silencing (RIGS) establishes the centromere structure, prevents the spread of transposons and silences transgenes, thereby limiting recombinant protein production. We previously isolated a sequence (B-3-31) that alleviates RIGS from the human genome. Here, we developed an assay system for evaluating the influence of repeat sequences on gene expression, based on in vitro ligation followed by our original gene amplification technology in animal cells. Using this assay, we found that the repeat of B-3-31, three core sequences of replication initiation regions (G5, C12, and D8) and two matrix attachment regions (AR1 and 32-3), activated the co-amplified plasmid-encoded d2EGFP gene in both human and hamster cell lines. This upregulation effect persisted for up to 82 days, which was confirmed to be repeat-induced, and was thus designated as a repeat-induced gene activation (RIGA). In clear contrast, the repeat of three bacterial sequences (lambda-phage, Amp, and ColE1) and three human retroposon sequences (Alu, 5'-untranslated region, and ORF1 of a long interspersed nuclear element) suppressed gene expression, thus reflecting RIGS. RIGS was CpG-independent. We suggest that RIGA might be associated with replication initiation. The discovery of RIGS and RIGA has implications for the repeat in mammalian genome, as well as practical value in recombinant production., Competing Interests: The authors have declared that no competing interests exist.

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

The free fatty acid receptor 1 (GPR40/FFAR1) is activated by polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acids (DHA). This receptor has been the focus of many studies regarding physiological functions of the central nervous system. PUFAs are essential for neuronal development and maintenance of neuronal function; thus, the decrease of PUFAs in the brain is closely related to the induction of psychiatric diseases associated with emotional disorder, such as anxiety, depression, and schizophrenia. However, details of the mechanisms remain unclear. In this study, we investigated changes of maternal and/or emotional behavior caused by a deficiency of GPR40/FFAR1 signaling. GPR40/FFAR1 deficient (FFAR1 -/- ) female mice exhibited impaired maternal care such as retrieving behaviors and an increased rate of neglect and infanticide when compared to wild type (WT) female mice. Furthermore, FFAR1 -/- female mice showed increased time spent in the open arms in an elevated plus maze test, reduction of locomotor activity and social interaction behavior, and decreased sucrose intake, when compared to WT female mice. In conclusion, these findings suggest that PUFAs-GPR40/FFAR1 signaling might function, at least in part, as a regulatory factor of emotional and maternal behavior in mice.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The present study was conducted to evaluate instrumental properties, to perform micro-structural analysis, and to research textural preference among Japanese general consumers (n=330) using raw and deep-fried peanuts with varying frying periods (2, 4, 6, 9, 12, and 15min) at 150°C. The relationship between consumer preference and the influence of gender and/or age among consumers regarding textural preference were evaluated. With increased frying time, the force at failure (FF) decreased from 26N to 18N, and the distance at failure (DF) decreased from 2.4mm to 1.0mm indicating increasing brittleness. A cross-sectional micro-structural image indicated increasing heterogeneity during frying. The mean preference score for 4min-, 6min-, 9min-, 12min-, and 15min-fried peanuts (3.0 to 3.4) exceeded that for 2min-fried peanuts (2.5 to 2.6), indicating that consumers liked easily broken peanuts. The tendency was more remarkable for middle-aged and elderly subjects (30years old and older) than for young subjects (15 to 29years old). Thus, textural perception may play a more important role in textural preference for older individuals than for young individuals. The Mann-Whitney's U test indicated no difference in textural preference between genders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The development of food that satisfies consumer preferences is very important for producing commodities. In the present study, 132 Japanese consumers carried out sensory evaluation of deep-fried peanuts with varying frying times (2, 4, 6, 9, 12 and 15 min) at 150 °C, and the relationships among sensory elements and physicochemical properties were investigated., Result: The sensory scores for colour, bitterness, and deep-fried peanut aroma increased (darker or stronger) with frying time, whereas the sweetness score was relatively high (strong) for frying times of 2, 4, 6 and 9 min, and then decreased (weaker) with increasing frying time. Frying times of 4, 6 and 9 min scored higher in overall liking than other times. Multiple-regression analysis indicated that the overall liking score was positively correlated with sweetness (standardised regression coefficient, β = +0.51) and deep-fried peanut aroma (β = +0.26) scores but negatively correlated with bitterness score (β = -0.25). Multiple-regression analysis also indicated a difference in sensory preference by gender. Sensory elements were closely related to the physicochemical properties, including the colour indexes (CIELAB colour space) and the sucrose and water contents. When L(*) (CIELAB colour space, lightness index) was 53-64 and water content was 10-30 g kg(-1), the mean overall liking score was relatively high implying acceptable fried peanut quality., Conclusion: Relationships among individual sensory elements were confirmed. Multiple-regression analysis indicated a strong positive correlation between sweetness and overall liking and a small difference in sensory preference by gender. Sensory evaluations can thus be expressed by physicochemical properties., (© 2013 Society of Chemical Industry.)

BAC FISH (fluorescence in situ hybridization using bacterial artificial chromosome probes) is a useful cytogenetic technique for physical mapping, chromosome marker screening, and comparative genomics. As a large genomic fragment with repetitive sequences is inserted in each BAC clone, random BAC FISH without adding competitive DNA can unveil complex chromosome organization of the repetitive elements in plants. Here we performed the comparative analysis of the random BAC FISH in monocot plants including species having small chromosomes (rice and asparagus) and those having large chromosomes (hexaploid wheat, onion, and spider lily) in order to understand a whole view of the repetitive element organization in Poales and Asparagales monocots. More unique and less dense dispersed signals of BAC FISH were observed in species with smaller chromosomes in both the Poales and Asparagales species. In the case of large-chromosome species, 75-85% of the BAC clones were detected as dispersed repetitive FISH signals along entire chromosomes. The BAC FISH of Lycoris did not even show localized repetitive patterns (e.g., centromeric localization) of signals., (© Springer-Verlag 2011)

'Florigen' was proposed 75 years ago to be synthesized in the leaf and transported to the shoot apex, where it induces flowering. Only recently have genetic and biochemical studies established that florigen is encoded by FLOWERING LOCUS T (FT), a gene that is universally conserved in higher plants. Nonetheless, the exact function of florigen during floral induction remains poorly understood and receptors for florigen have not been identified. Here we show that the rice FT homologue Hd3a interacts with 14-3-3 proteins in the apical cells of shoots, yielding a complex that translocates to the nucleus and binds to the Oryza sativa (Os)FD1 transcription factor, a rice homologue of Arabidopsis thaliana FD. The resultant ternary 'florigen activation complex' (FAC) induces transcription of OsMADS15, a homologue of A. thaliana APETALA1 (AP1), which leads to flowering. We have determined the 2.4 Å crystal structure of rice FAC, which provides a mechanistic basis for florigen function in flowering. Our results indicate that 14-3-3 proteins act as intracellular receptors for florigen in shoot apical cells, and offer new approaches to manipulate flowering in various crops and trees.

Background. To investigate the effect of social service prenatal care (PNC) utilization on perinatal outcomes among women with socioeconomic problems in the Tokyo metropolitan area. Methods. Retrospective study. The study enrolled all women at our hospital who either attended PNC utilizing social services (attenders) or who did not attend PNC (nonattenders) between January 1, 2007, and December 31, 2010. We compared the maternal characteristics and perinatal outcome of attenders with those of nonattenders. Results. A total of 83 attenders and 45 nonattenders were enrolled. The mean gestational age at the first PNC visit was 31.1 weeks in the attenders. Attenders were found to have a lower incidence of preterm delivery, pregnancy-induced hypertension, emergency cesarean section, low birth weight, and the NICU admission than nonattenders (P < 0.05). Conclusions. The utilization of social service PNC greatly improved perinatal outcomes among women with socioeconomic problems problems in the Tokyo metropolitan area.

Objective: Estrogen is involved in the development of breast and endometrial cancers, and tamoxifen, an antiestrogen, is associated with an increased risk of endometrial cancer. Recently, tamoxifen use is suggested to be associated with the development of aggressive endometrial tumors. We performed a retrospective study to clarify the effects of tamoxifen (TAM) and toremifene (TOR) on clinicopathological features of endometrial cancer subsequently developed in breast cancer patients., Methods: Endometrial cancer patients diagnosed at our institution from 2000 through 2008 were studied., Results: Of 194 patients with endometrial cancer, 18 (9.3%) developed breast cancer before endometrial cancer diagnosis. Mean age was 66 years, and the median time interval between breast and endometrial cancer diagnosis was 10 years (range, 1.5 -32 years). Nine patients developed aggressive tumors(serous, clear cell, small cell carcinoma, and carcinosarcoma), and the remaining nine developed endometrioid tumor. Patients with aggressive tumor had a lower 5-year disease-specific survival (0% vs 88%, p<0.01). Ten patients had used TAM and/or TOR, and six had not; aggressive tumors developed in six of 10 TAM/TOR users, and in one of six nonusers (p=0.15), and the 3-year disease-specific survival rate was not different between TAM/TOR users and nonusers (62% vs 53%, p=0.84). Time intervals from breast cancer and endometrial cancer diagnosis were 10-16 years for TAM users and 5-6 years for TOR users (p=0.02)., Conclusion: Tamoxifen/toremifene use for breast cancer did not affect the prognosis of subsequent endometrial cancer in our small study; however, further studies were warranted. The use of toremifene may be associated with a shorter interval from breast cancer to endometrial cancer diagnosis compared to tamoxifen.

Hd3a and FT proteins have recently been proposed to act as florigens in rice and Arabidopsis, respectively; however, the molecular mechanisms of their function remain to be determined. In this study, we identified GF14c (a 14-3-3 protein) as an Hd3a-interacting protein in a yeast two-hybrid screen. In vitro and in vivo experiments, using a combination of pull-down assays and bimolecular fluorescence complementation, confirmed the interaction between Hd3a and GF14c. Functional analysis using either GF14c overexpression or knockout transgenic rice plants indicated that this interaction plays a role in the regulation of flowering. GF14c-overexpressing plants exhibited a delay in flowering and the knockout mutants displayed early flowering relative to the wild-type plants under short-day conditions. These results suggest that GF14c acts as a negative regulator of flowering by interacting with Hd3a. Since the 14-3-3 protein has been shown to interact with FT protein in tomato and Arabidopsis, our results in rice provide important findings about FT signaling in plants.

The decrease in viscosity is widely used to estimate the activity of pectinolytic enzymes. This method is shown to be influenced by the production strain and this prevents an accurate comparison between the activities of different microorganisms, especially under different conditions.

Beraprost sodium (sodium (+/-)-(1R*,2R*,3as*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its general pharmacological effects on peripheral organs were studied. 1. In isolated organs, beraprost sodium relaxed the trachea and increased atrial beating rate (2.4 x 10(-5) mol/l). It also dose-dependently contracted the stomach, aorta, ileum and uterus (2.4 x 10(-7)-2.4 x 10(-4) mol/l). These effects of beraprost sodium were similar, but inferior to those of PGI2 and PGE1. 2. Intravenous administration of beraprost sodium produced a dose-related decrease in blood pressure (BP), its potency being about 1/3 times that of PGI2 in anesthetized rats and dogs. Beraprost sodium and PGI2 had no effects on heart rate (HR), and enhanced respiration in conjugation with a decrease in BP. Oral administration of beraprost sodium in high doses (1-3 mg/kg in rats and 0.3 mg/kg in dogs) caused a decrease in BP. A compensatory tachycardia and an elevated plasma renin activity (PRA) occurred after low doses (0.1-0.3 mg/kg) in rats. In contrast, a change of HR and PRA in rabbits and dogs was mild. 3. Beraprost sodium produced suppression of digestive organs: markedly, gastric motility and secretion and intestinal transport; slightly, but significantly, biliary secretion. On the other hand, it enhanced ileal motility at a high dose (300 micrograms/kg i.v.). 4. Oral administration of beraprost sodium caused a decrease in urinary volume and electrolyte excretion in rats. 5. Oral administration of beraprost sodium prolonged bleeding time in mice, while it had no effect on the blood coagulation system in vitro. In addition, beraprost sodium had no hemolytic action. 6. The other effects of beraprost sodium were weak. Beraprost sodium had no local anesthetic activity and no effect on salivation, pupil size and neuromuscular transmission in the skeletal muscle. Beraprost sodium slightly contracted the uterus of non-pregnant rats in situ and dose-independently inhibited carrageenin-induced paw edema. In conclusion, beraprost sodium produced various effects on the autonomic, cardiovascular, and gastrointestinal systems. Probably, these effects may be based on its own action like PGI2.