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Background/aims ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ONO-9054 with the FP agonist Xalatan. Methods Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0.003%, 30 μg/mL) or Xalatan (0.005%, 50 μg/mL) once daily for 28 days. Results Day 29 mean diurnal IOP was −7.2 mm Hg for ONO-9054 vs −6.6 mm Hg for Xalatan. At 08:00 hours, the IOPs were comparable, and at all later time points the decrease in IOP was greater for ONO-9054. On day 29, the odds of a mean IOP reduction of ≤−25%, ≤−30% and ≤−35% for ONO-9054 were 2.39, 2.37 and 4.85 times more, respectively, than the odds for Xalatan (p

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 dose-limiting 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.

Purpose The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E 2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers. Methods In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day –1 to Day 2), and at the follow-up visit (Day 7 [±2 days]). Findings Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001–0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine. Implications In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.

With current losses of saltmarsh running at > 100 ha per year in the UK, creation of new intertidal habitats through managed realignment is likely to be increasingly used. Potentially, this has biodiversity as well as engineering benefits. However, assessing the conservation value of many of the current UK schemes is difficult as the biological monitoring has been generally poor, with a few notable exceptions. At the Tollesbury and Orplands realignment sites, Essex, bird communities were dominated by terrestrial species during the first year of inundation and waterbird communities rapidly developed during the second and third years. Five years after the initial breach in the sea wall, communities were similar to surrounding mudflats but with some notable exceptions. Dunlin Calidris alpina and Common Redshank Tringa totanus that prey on the early colonizing Nereis and Hydrobia used the sites in the first 2 years. Eurasian Oystercatcher Haematopus ostralegus did not occur on the realignment site as there were no large bivalves, whereas Red Knot Calidris canutus used the site after 4–5 years coincidentally with the appearance of Macoma balthica. The differences in the bird communities occurred because UK sites are often small, enclosed and poorly drained. If at a suitable height in the tidal frame, UK managed realignment sites are successful in that they have developed saltmarsh and biologically active mudflats but they may lack the full range of biodiversity found in surrounding natural intertidal habitats, even decades after inundation.

We describe a slow-open analytic group for male survivors of childhood sexual abuse and emphasize the importance of having both a male and a female co-conductor The Beck Depression Inventory and the Spielberger State Anxiety Scale were used as an outcome audit before and after the group and at six months follow-up. The results supported the clinical impression of overall improvement. We record similarities and distinguishing features between this group and a group for women survivors in which three of the authors had previously been engaged as co-conductors.

A sustained-release tablet (SRT) of ONO-5334 was compared to the immediate-release tablet (IRT) dose, which demonstrated effects on bone mineral density (BMD) comparable to those of therapy with alendronate. The single-dose phase was a randomized, partial single-blind, crossover study where 50-, 100-, and 300-mg SRTs and 300-mg IRTs were administered to nine post-menopausal women. The multiple-dose phase was a randomized, double-blind, placebo-controlled, parallel-group study where 100- and 300-mg SRTs, or placebo were administered to 24 women. After a single administration of a 300-mg SRT, mean C max was 3.3-fold lower, mean AUCinf was 0.83-fold lower and mean C 24h was 5.4-fold higher compared to the 300-mg IRT. Repeated SRT dosing did not significantly affect PK, although C 24h increased slightly. After a single ONO-5334 dose, serum CTX-I was suppressed by ~50 % within 1 h, reaching maximum suppression 6 h post-dose. Greater suppression was maintained longer by the 300-mg SRT vs. the 300-mg IRT. Second morning void and cumulative urine CTX-I showed clear dose–response effects at/over 24 h for SRT, with maximum suppression occurring at/over 24 h (except 50- and 300-mg cumulative urine). Repeated dosing suggested greater suppression of urine CTX-I. Compared with the IRT, the SRT showed reduced C max, greater C 24h, and slightly reduced AUCinf dose for dose. The SRT showed clear dose–response suppression on bone resorption and greater efficacy dose for dose vs. the IRT.

A simple experiment in optical interferometry is described that utilizes a small telescope or binoculars and streetlights as the sources. The experiment can be used to estimate the size of distant streetlights and to explain the principle of the Michelson stellar interferometer.

The resolution of countertransference through the supervisory seminar, illustrating the dynamics of an observable change in the conductor and in the group.

Introduction Bruton’s tyrosine kinase (BTK) is a critical kinase involved in B-cell receptor signal transduction. ONO-4059, a highly potent and selective oral BTK inhibitor has demonstrated anti-tumour activity in pre-clinical models (Yasuhiro et al, AACR2013) and in the clinic in both CLL and NHL patients (Morschhauser et al, EHA 2014; Rule et al, EHA 2014). Here, we present data from 25 CLL patients enrolled in the ongoing Phase I study ONO-4059POE001. Methods Twenty five CLL patients were administered ONO-4059 as monotherapy, given once daily (QD) to determine safety, pharmacokinetics and pharmacodynamics, and preliminary efficacy. Patients can receive ONO-4059 for up to a maximum of 3 years and upon completion of the first 6 months of treatment, intra-patient dose escalation is permitted. Here, we present data for 25 evaluable patients treated with ONO-4059 at doses ranging from 20-600mg (8 cohorts). Patients had a median age 67 yrs [range 40-79], median baseline tumour burden 3,943 mm2 [461-19,750 mm2], median of 4 prior therapies [2-8], including fludarabine (23/25) and rituximab-containing therapy (23/25). Baseline median haematology parameters included lymphocytes 34.6 x 109/L [0.1-391], haemoglobins 11.1 g/dL [8.5-15.2], platelets 97 x 109/L [23-185], neutrophils 2.39 x 109/L [0.5-11.1]. 9/24 patients were 17p deleted [38%] and 6/24 had the 11q deletion [25%], 20/24 were IgVH unmutated status [83%], with 13/24 [54%] displaying TP53 mutation). Results To date, 19 of 25 patients remain on treatment with a median duration of treatment of 363 days [27-659]. ONO-4059 was found to be well tolerated with few adverse reactions over a long duration. A total of sixty two ONO-4059-related Grade 1- 2 adverse events were reported in 19 out of 25 patients. Eight dose independent ONO-4059-related G3 or G4 haematological toxicities were reported in 5 patients; with neutropenia in 3 patients, [G3 x 1, G4 x 2]), febrile neutropenia in 1 patient [G3] and leucopenia in 2 patients [G3 x 4]. Six Grade 3 ONO-4059-related non-haematological events were reported (pyrexia x 1, Hepatitis E reactivation x 1, Lymphocytic infiltration, Purpura, Urinary tract infection and Haematoma in just one patient). Nine ONO-4059-related SAEs were reported in 6 patients (febrile neutropenia [G3] and pyrexia [G3] at 20 mg, rash [G2] at 80 mg, hepatitis E reactivation [G3] at 320mg, neutropenia [G4] at 320 mg, purpura x 2 [G2, G3] and lymphocytic infiltration [G3] at 400 mg, haematoma [G2] at 500mg). All patients experienced rapid reductions in lymphadenopathy observed early in treatment between Cycle1 and Cycle3, accompanied by an increase in absolute lymphocyte count in 72% of patients. Almost all patients have durable response over a long duration. Best overall response rate according to IWCLL criteria (including modified PR with lymphocytosis) was 84% [based on CT-scan and P/E for 21/25 evaluable patients with 17 PR, 4 PR with lymphocytosis (for 21 responding patients, median reduction of lymph nodes was 83% [51-100]), 1 SD and 2 PD], with 89% response rate on 17p deleted. The early tumour shrinkage was associated with a rise in haemoglobin and platelet count. An increase in exposure (as assessed by Cmax and AUC) that was proportional to an increase in dose was seen for all doses of ONO-4059 ranging from 20-600mg. Conclusion ONO-4059 is a highly potent and selective oral Btk inhibitor with a favourable safety profile along with promising efficacy over a long duration in this heavily pre-treated population, with responses observed in relapsed, refractory and currently poor prognostic 17p deleted patients. Disclosures Fegan: ONO PHARMA: Honoraria. Salles:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:ONO PHARMA: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:ONO PHARMA: Research Funding. Cartron:ONO PHARMA: Honoraria. Honda:Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Yoshizawa:Ono Pharmaceutical Co., Ltd.: Employment.

1. Change invariably occurs following a crisis, which enables a new paradigm to be adopted. 2. Religious faith may be one possible paradigm that may be of benefit to patients. 3. Nurses have a responsibility to explore this untapped potential with their patients. 4. A patient with severe phobic anxiety who made a sustained positive response to becoming a Christian is described.

A systematic inventory and test of the area defined as 32ME588 was conducted from April 30 to May 1,1995. The purpose was to assess the eligibility of 32ME588 for nomination to the National Register of Historic Places. The site is located on the south bank of Lake Sakakawea in Mercer County, North Dakota, on the Corps' shoreline and take area as part of the Hille State Game Management Area. The area is only occasionally used by fishing parties and for wildlife and cattle grazing. (MM)

The purpose of performing a systemic inventory and testing of site 32DU4l3 was to gather sufficient information to assess the eligibility of the site for nomination to the National Register of Historic Places (NRHP). The inventory was conducted from April 24 to April 29, 1995, in the Little Missouri public Use area which is bordered on the north by the Little Missouri arm of Lake Sakakawea and on the west by Little Missouri Bay. The Andrus Resort area was also included because of scheduled construction activities. In general, the site does not appear to be eligible for nomination to the NRHP. This includes all of the areas within Andrus Resort that are scheduled for development. Archeological clearance for these developments is recommended without additional cultural resource stipulations. (MM))

Adaptive resonance theory (ART) neural networks are becoming an important component of neural network industrial applications. Electronic implementation of these network models has proven difficult to scale to practical input dimensionality. In this paper, a new implementation of ART1 is proposed that efficiently combines optical and electronic devices. Global computations are performed by the optics, while local operations are performed in electronics. A physical implementation of this architecture that uses ferroelectric liquid crystal modulators integrated with VLSI circuitry is presented.1 The system has the capacity to learn in real time and to store the neural weights in a two dimensional optically addressed smart spatial light modulator (SSLM). The implementation can be packaged in a multi-chip module of small physical dimensions. Macro-circuits can be constructed from these modules to perform complex logical functions. This system can also be modified to allow read-out and readin of the learned weights stored in the SSLM, for replication of trained systems. The sensitivity of the ART1 network algorithm to variations in modulator and detector device characteristics is discussed.

A single crystal X-ray diffraction study has established that [Fe(CO)3{(CF3)2-C2S2}] exists as a dimer in the solid state. Mossbauer parameters for this compound and its derivatives [Fe(CO)2(PPh3){(CF3)2C2S2}], [Fe(CO)(PPh3)2{(CF3)2C2S2}] and [Fe(CO)(dppe){(CF3)2C2S2] are reported, and compared with those of [Fe2-(CO)6(SPH)3]PF6 and [Fe2(CO)6(SPh)2].

La honte est une notion pivot pour les Melanesiens. Chez les Orokaiva il n'est aucun aspect de l'existence qui n'echappe a son impact: relations intimes et familiales, affaires de clan et de tribus, bref tous les domaines qui ont a voir avec la culture, la religion et la politique. Elle renforce les tabous; elle forme la trame du folklore; elle determine et renforce le statut social. Dans cette societe totalement fondee sur la reciprocite «l'echange de honte» - [comment l'eviter, la manipuler, la contenir et la distribuer] - est le tissu meme de la vie

8553 Background: Bruton’s tyrosine kinase (BTK) is a critical kinase involved in B-cell receptor signal transduction. ONO-4059, a highly potent and selective oral BTK inhibitor has demonstrated ant...