Key Points• We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.• ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/ refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a doselimiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. (Blood. 2016;127(4):411-419)

Period2 (Per2) is an essential component of the mammalian clock mechanism and robust circadian expression of Per2 is essential for the maintenance of circadian rhythms. Although recent studies have shown that the circadian E2 enhancer (a non-canonical E-box) accounts for most of the circadian transcriptional drive of mPer2, little is known about the other cis-elements of mPer2 oscillatory transcription. Here, we examined the contribution of E4BP4 to Per2 mRNA oscillation in the cell-autonomous clock. Knockdown experiments of E4BP4 in both Northern blots and real-time luciferase assays suggested that endogenous E4BP4 negatively regulates Per2 mRNA oscillation. Sequence analysis revealed two putative E4BP4-binding sites (termed A-site and B-site) on mammalian Per2 promoter regions. Luciferase assays with mutant constructs showed that a novel E4BP4-binding site (B-site) is responsible for E4BP4-mediated transcriptional repression of Per2. Furthermore, chromatin immunoprecipitation assays in vivo showed that the peak of E4BP4 binding to the B-site on the Per2 promoter almost matched the trough of Per2 mRNA expression. Importantly, real-time luciferase assays showed that the B-site in addition to the E2 enhancer is required for robust circadian expression of Per2 in the cell-autonomous clock. These findings indicated that E4BP4 is required for the negative regulation of mammalian circadian clocks.

We systematically studied the catalytic activity of the oxygen evolution reaction (OER) for the tetragonal spinel oxide Mn3-xCoxO4 (0 ≤ x < 1 and 1 < x ≤ 1.5). The OER catalytic activity of Mn3-xCoxO4 (0 ≤ x < 1) dramatically improved with an increase in Co content. We found that the OER activity of Mn3-xCoxO4 (0 ≤ x < 1) increased linearly with the suppression of the Jahn-Teller distortion. We therefore propose that the Jahn-Teller distortion plays an important role in the OER activities of compounds containing Mn 3+ . Mn3-xCoxO4 (0 ≤ x < 1) provides a rare case for directly studying the effect of the Jahn-Teller distortion on OER activity.

Although Bmal1 is a key component of the mammalian clock system, little is understood about the actual mechanism of circadian Bmal1 gene transcription, particularly at the chromatin level. Here we discovered a unique chromatin structure within the Bmal1 promoter. The RORE region, which is a critical cis element for the circadian regulation of the Bmal1 gene, is comprised of GC-rich open chromatin. The 3-flanking region of the promoter inhibited rhythmic transcription in the reporter gene assay in vitro even in the presence of ROR␣ and REV-ERB␣. We also found that the nuclear matrix protein SAF-A binds to the 3-flanking region with circadian timing, which was correlated with Bmal1 expression by footprinting in vivo. These results suggest that the unique chromatin structure containing SAF-A is required for the circadian transcriptional regulation of the Bmal1 gene in cells.Circadian rhythms in behavior and physiology have an adaptive significance for living organisms from bacteria to humans and reflect the existence of an underlying intrinsic circadian oscillator or biological clock (10). The master clock that generates circadian rhythms in mammals is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In turn, peripheral clocks directly regulate many local rhythms that probably feed back to the SCN through hypothalamic integration (5). The molecular mechanism of the circadian oscillator consists of autoregulatory transcriptional and translational feedback loops that have both positive and negative elements (10). The key transcription factors, CLOCK and BMAL1, form heterodimers that bind to E-box enhancer sequences and activate the transcription of the three Period genes (Per1, Per2, and Per3) and two Cryptochrome genes (Cry1 and Cry2) (46). The PER and CRY proteins subsequently repress transcription at their own promoters through negative feedback caused by acting on the CLOCK-BMAL1 complex (35). This feedback loop system controls the central clock in the SCN and the peripheral clocks in most peripheral tissues (18).Originally, BMAL1 (also known as MOP3) was characterized by high expression levels in brain and muscle cells (16). As the activity of Bmal1 Ϫ/Ϫ mice immediately becomes completely arrhythmic in constant darkness, BMAL1 is apparently an essential and nonredundant component of the mammalian clock (6). The level of Bmal1 transcripts robustly oscillates in the SCN and in peripheral clock cells (25), and the circadian regulation of Bmal1 transcription contributes to the formation of interconnected feedback loops (35). The Bmal1 promoter contains two recognition motifs for ROR and REV-ERB orphan nuclear receptors (ROREs). Preitner et al. reported that REV-ERB␣, which represses Bmal1 expression, is the major regulator of cyclic Bmal1 transcription (31), and Akashi and Takumi described that ROR␣ acts to promote Bmal1 transcription (1). The opposing activities of the orphan nuclear receptors ROR␣ and REV-ERB␣ are important in the maintenance of circadian clock function (34). It was also suggested...

Sr2VFeAsO3−δ remarkably enhances the oxygen evolution reaction by direct O–O bond formation between OH− coupled oxygen-vacant sites.

A pharmacokinetic model for aprepitant has been developed that incorporates body weight, age, ALT, BUN and aprepitant dose to predict the CL/F. The results of population pharmacokinetic analysis of dexamethasone support dose adjustment of dexamethasone in the case of co-administration with aprepitant.

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