JADE Research Articles

Abstract B18: Quantification of BTK engagement by ibrutinib in peripheral blood mononuclear cells in a phase I clinical study.

Abstract Introduction: Bruton's tyrosine kinase (BTK) is a TEC-family receptor tyrosine kinase essential for B-cell receptor signaling and is critical for the growth and survival of several types of B-cell malignancies. Ibrutinib (PCI-32765) is a selective, oral, small molecule inhibitor that binds covalently to the active site of BTK (Cys481). Ibrutinib has been designated as a breakthrough targeted therapy for certain types of B-cell malignancies and is approved by the US Food and Drug Administration for patients with previously treated mantle cell lymphoma and chronic lymphocytic leukemia. As ibrutinib is being tested in various malignancies and multiple patient populations, it is important to understand its target engagement at different doses. Therefore, a novel, sensitive, and robust assay was developed to study target engagement on the Meso Scale Discovery (MSD) platform and used to study BTK occupancy in a Phase 1 clinical study of ibrutinib in combination with R-CHOP in B-cell Non-Hodgkin lymphoma patients (DBL1002; NCT01569750) which is described in detail elsewhere (Younes et al ASH 2013). Description: This target engagement assay determines the relative amount of free unbound BTK by using a probe. The BTK molecules that are not already bound to ibrutinib bind to the probe while the remaining sample is washed off. Free BTK is assessed using an anti-BTK antibody, and total signal is detected using the MSD Sector Imager 6000 as relative light units (RLU). Summary of Results: Final results in RLU are inversely related to free BTK. The assay was developed and successfully validated to interrogate PBMC lysates as the matrix of choice, using the BTK standard as a reference. The assay was used to test PBMC samples from the clinical study DBL1002. PBMC samples collected from patients (N=9) treated at the recommended dose of 560mg were measured prior to and 4 hrs after the first dose of ibrutinib. The median value for Btk occupancy at pre-treatment was 825.357 pg/mL, while 4 hours after the first dose of ibrutinib the median value dropped to 11.25 pg/mL, indicating full occupancy of BTK. Conclusions: Treatment with ibrutinib at a dose of 560mg in combination with R-CHOP led to complete inhibition of BTK 4 hours after the first dose of ibrutnib. These results were consistent with previous results from single agent trials using the gel-based assay for BTK occupancy, indicating that the additional chemoimmunotherapy did not interfere with ibrutinib binding to its target BTK. Citation Format: Shalini Chaturvedi, Cuc Davis, Stella Chang, Mint Sirisawad, Jan de Jong, Betty Chang, Anas Younes, Nele Fourneau, Sriram Balasubramanian, Brett Hall. Quantification of BTK engagement by ibrutinib in peripheral blood mononuclear cells in a phase I clinical study. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B18.

Abstract B19: Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies.

Abstract Ibrutinib (IBRU) is an oral Bruton's tyrosine kinase (BTK) inhibitor, approved by US FDA for the treatment of chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) patients having received at least one prior therapy. A nonlinear mixed-effects population model was developed to describe the PK of IBRU in patients with B-Cell malignancies and to establish the effect of pathophysiological covariates on its PK behavior. The relationship between PK and BTK engagement in peripheral blood mononuclear cells (PBMC) was also explored. IBRU PK data (3477 observations in 245 patients) were available in patients with MCL, CLL/SLL and recurrent B-cell malignancies at dose levels from 1.25 to 12.5 mg/kg and at fixed doses from 420 to 840 mg once daily. An additional phase 2 study in 119 patients with MCL (772 observations) treated at 560 mg once daily was used to validate the PK model. BTK occupancy was assessed (694 observations in 127 patients) in PBMCs using a fluorescent affinity probe. Various models were tested on the data using the first-order conditional estimation method as implemented in NONMEM version 7.1. A 2-compartment linear model with sequential zero-first order absorption and first order elimination was able to accommodate available PK data, including those of the validation dataset (prediction errors <15%). PK was dose- and time- independent. IBRU was rapidly absorbed, extensively distributed (volume of distribution at steady-state ~ 10,000 L) and cleared (apparent oral clearance ~1000 L/h). Relative bioavailability in the fasting state was about one third lower compared to the fed condition used in the clinical trials. No significant effect of other pathophysiological covariates on the PK was found (including sex, age or indication) except for body weight and coadministration of antacids, which had a marginal effect on the volume of distribution and duration of absorption, respectively. Analysis of PK-BTK engagement suggested that IBRU is a potent inhibitor of the BTK activity and that its interaction with BTK is rapid and durable. Citation Format: Italo Poggesi, Maria Luisa Sardu, Eleonora Marostica, Juthamas Sukbuntherng, Betty Y. Chang, Jan de Jong, Xavier Woot de Trixhe, An Vermeulen, Giuseppe De Nicolao, Susan Mary O'Brien, John C Byrd, Ranjana H Advani, Danelle Frances James, William Deraedt, Darrin Beaupre, Michael Wang. Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B19.

Abstract B20: Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study.

Abstract Background: Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase, and is extensively metabolized by CYP3A. No subjects with clinically significant hepatic impairment have been enrolled in the clinical efficacy and safety studies performed to date and more data are needed to understand the safety of ibrutinib in this patient population. Methods: This was an open-label, multi-center, single-dose study in 30 subjects with pharmacokinetic (PK) sampling up to 96 h postdose. Ibrutinib was administered orally at 140 mg following an overnight fast to non-cancer subjects with mild (n=6), moderate (n=10), and severe (n=8) hepatic impairment according to Child-Pugh, and to age- and weight-matched control subjects (n=6). Results: Subjects with mild, moderate, and severe hepatic impairment, but who were otherwise healthy, showed a significant increase in ibrutinib plasma exposures, as well as fraction unbound ibrutinib, with increasing impairment. Regardless of the severity of hepatic impairment, ibrutinib plasma concentration versus time profiles showed an elimination profile with an initial rapid decline which became gradual towards the terminal phase. Compared to control subjects, mean unbound exposure (AUClast,unbound) in the mild, moderate, and severe cohorts was 4.4-, 9.6-, and 13-fold higher. Compared with normal hepatic function, Cmax of unbound ibrutinib increased 5.7- to 9.9- fold with increasing hepatic impairment. Terminal half-life trended slightly higher in moderately and severely impaired subjects, but the risk for accumulation on repeated dosing appears negligible as half-life did not exceed 10 hours. Urinary excretion of unchanged ibrutinib, although increasing with severity of hepatic impairment, remained negligible at << 1% of the dose. A single dose of 140 mg was well tolerated in this study. Conclusion: Based on the observed effect on plasma exposure, the recommended doses for patients with mild and moderate liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A and B), respectively. Since no lower capsule strengths are currently available, it is not recommended to administer ibrutinib to patients with severe liver impairment (Child-Pugh Class C). Citation Format: Donna Skee, Jan De Jong, Peter Hellemans, Dominique Swerts, Deborah Conover, Christopher Jones, Eric Lawitz, Thomas Marbury, William Smith, Vijay Chauhan, Juhui James Jiao, Juthamas Sukbuntherng, Erik Mannaert. Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B20.

Abstract CT302: Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: ARN-509 and AA target the androgen axis via different mechanisms and may have complementary activity in mCRPC. ARN-509, a potent and selective androgen receptor (AR) antagonist, inhibits AR nuclear translocation and DNA binding without significant AR agonist properties (Clegg et al. Cancer Res. 2012). AA is the prodrug of abiraterone, which directly inhibits androgen biosynthesis. No overlapping toxicities are expected for the combination. This ongoing phase Ib study evaluates the potential PK drug-drug interaction and safety of ARN-509 in combination with AA + P. Methods: Pts had progressive mCRPC and ECOG score ≤ 2. Pts received AA (1000 mg/d) + P (5 mg BID) beginning on Cycle 1 Day 1 (C1D1) with the addition of ARN-509 (240 mg/d) on C1D8 in 28-day treatment cycles until disease progression or toxicity. Serial blood samples for PK analysis were collected on C1D7 and C2D8 for abiraterone analysis and on C2D8 for ARN-509 analysis. Primary objective: evaluate effect of ARN-509 on abiraterone PK. Secondary objective: evaluate safety of ARN-509 in combination with AA + P. Results: As of November 21, 2014, 28 pts have been enrolled. At baseline, the median age was 70 years (range: 49-83); median prostate-specific antigen was 56.8 μg/L (range: 4.1-2597.0 μg/L); bone, nodal, and visceral disease were present in 24 (86%), 17 (61%), and 8 (29%) pts; and 13 (46%) pts were pretreated with docetaxel, 11 (39%) with AA, and 12 (43%) with enzalutamide. 9 pts thus far completed 1 cycle, 6 completed 2 cycles, and 4 completed 3 cycles. 26 pts are continuing therapy. 10 pts were evaluable for PK assessment and 28 pts were evaluable for safety assessment. Most drug-related adverse events (AEs) were grade 1-2, and included fatigue (n = 5), diarrhea (n = 3), dysgeusia (n = 3), vomiting (n = 4), abdominal pain (n = 2), anorexia (n = 3), dyspepsia (n = 2), rash (n = 2) and nausea (n = 3). Grade 3 drug-related AEs included hyponatremia (n = 1), fatigue (n = 1), and increased alanine aminotransferase (n = 1), and were managed by drug interruption and supportive measures. Interim data indicate a small reduction in abiraterone PK exposure when AA + P is coadministered with ARN-509. PK of ARN-509 were consistent with historical data when ARN-509 was given as monotherapy. Conclusions: This ongoing phase Ib study (NCT02123758) indicates no clinically significant PK interaction between ARN-509 and AA + P. The combination is well tolerated in pts with mCRPC; interim AE data were consistent with those seen in the AA + P phase III trials (Fizazi et al. Lancet Oncol. 2012; Ryan et al. NEJM. 2013). These preliminary results justify further evaluation of the safety and efficacy of ARN-509 in combination with AA + P for mCRPC. Citation Format: Edwin M. Posadas, Kim N. Chi, Ronald de Wit, Maja JA de Jonge, Gerhardt Attard, Terence Friedlander, Margaret Yu, Peter Hellemans, Caly Chien, Charlene Abrams, Martha Gonzalez, Géralyn C. Trudel, Vijay Chauhan, Fred Saad. Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT302. doi:10.1158/1538-7445.AM2015-CT302

Jan de Beer’s Lifetime Reputation and Posthumous Fate

Recommended Citation: Dan Ewing, “Jan de Beer’s Lifetime Reputation and Posthumous Fate,” JHNA 7:2 (Summer 2015) DOI: 10.5092/jhna.2015.7.2.1 Available at http://www.jhna.org/index.php/vol-7-2-2015/314-dan-ewing Published by Historians of Netherlandish Art: http://www.hnanews.org/ Terms of Use: http://www.jhna.org/index.php/terms-of-use Notes: This PDF is provided for reference purposes only and may not contain all the functionality or features of the original, online publication. This PDF provides paragraph numbers as well as page numbers for citation purposes. ISSN: 1949-9833 Journal of Historians of Netherlandish Art

Correspondence Analysis and West Mexico Archaeology: Ceramics from the Long-Glassow Collection. By C. Roger Nance, Jan de Leeuw, Phil C. Weigand, Kathleen Prado and David S. Verity. (2013) Albuquerque: University of New Mexico Press.

Correspondence Analysis and West Mexico Archaeology: Ceramics from the Long-Glassow Collection. By C. Roger Nance, Jan de Leeuw, Phil C. Weigand, Kathleen Prado and David S. Verity. (2013) Albuquerque: University of New Mexico Press.

The Maritain Factor: Taking Religion into Interwar Modernism ed. by Rajesh Heynickx and Jan De Maeyer (review)

Maritain Factor: Taking Religion into Interwar Modernism. Edited by Rajesh Heynickx and Jan De Maeyer. [KADOC Studies on Religion, Culture and Society, 7.] (Leuven: Leuven University Press. Distrib. Cornell University Press. 2010. Pp. 211. $42.50 paperback. ISBN 978-90-5867-714-3.)This strong collection of essays fills an important niche in Maritain studies. Through its consideration of the interwar period during which Jacques and Raisa Maritain first launched their apostolate to culture, these authors do much to illuminate the interplay of the aesthetic, religious, philosophical, and political aspects of the crucial decades preceding World War II. Maritain works best known to American readers were written during the two decades after World War II. Therefore, this collection of essays would assist such readers to appreciate the broader perspectives as well as the origins of Maritain's later work.The collection includes both overviews of the Maritains' work and studies of particular relationships and specific trends and movements. These essays are well informed, and they unearth new details about the important relationships of the age. Most of all, the authors develop fresh interpretations of their life and work. editor, Rajesh Heynickx, seeks to break with the schematic and myopic views (p. 14) of Maritain that either consign him to irrelevance because of his Catholicism and Thomism, as well as those who lionize him as the privileged way into the recovery of revitalized philosophy. What they both miss, he claims, is the concrete historical dimension that would make possible such a tremendous impact of a philosopher of fixed principles (p. 14) and eternal perspective on the practices and discourse of the modernists who celebrated change and fragmentariness.Exploring Maritain's own paradoxical claim to be both antimodern and ultramodern, the many essays in book considers how Maritain's Thomism and devout Catholicism led him to friendships and significant dialogue with many of the leaders of modern art, literature, and culture. Stephen Schloesser's The Rise of a Mystic Modernism presents a nice summary of the discoveries and hypothesis of his book Jazz Age Catholicism (Toronto, 2005). In sum, he explores how the very distinction between matter and form opened Maritain to a variety of ways of manifesting the form in diverse materials, style, and approaches. Rather than imitate the past in a neo-Gothic style, modernism could be seen as a way to explore new manifestations of the personal being, the search for God, and the conflict of good and evil. In addition, the modernist struggles with the guilt of war would lead to a reparation for the dead in fitting tribute to the young lives sacrificed in the horror of war. …

Plastid thieves escape starvation

Symbiosis![Figure][1] Ingested algae pitch in to prevent starvation CREDIT: JAN DE VRIES AND STEFFEN KOHLER/CAI Green sea slugs feed on algae, and in the process they take up photosynthetic plastids from the algae. The plastids stay intact in the slug's gut cells for months, and the slugs benefit nutritionally from ongoing photosynthesis. So much so that that some scientists think that the plastids can prevent slugs from dying of starvation. But photosynthesis and starvation can also produce toxic products that cause the slugs to die. de Vries et al. found one species of slug that does not rely on photosynthesis to keep it going during hard times. This slug resists death by ramping up mechanisms to remove damaged plastids and toxins. Proc. R. Soc. B 10.1098/rspb.2014.2519 (2015). [1]: pending:yes

Tales from the Crypt: On Some Uncharted Voyages of Sindbad the Sailor Introduction

IntroductionThe Seven Voyages of Sindbad, also known as the Seaman and the Landsman are among the most well known tales of the Arabian Nights. The tales were not part of the famed Galland Manuscript dating from the middle of the fijifteenth century (Marzolph and Van Leeuvan 2: 635). Rather, Antoine Galland (d. 1715) discovered manuscripts of the work during his travels in Turkey. (Mahdi 17-20; Marzolph Sindbad der Seefahrer, 701). Galland was sufffijiciently impressed with these tales to prepare a full translation that he placed at the beginning of the third volume of Les Milles et une Nuit published in 1704 (Galland 228-91).For the past three centuries scholars have attempted to date the collection. Enlightenment readers of the tales beginning with Galland argued for their antiquity focusing on particular themes such as Sindbad's encounter with a Cyclops that suggested their links to Homer's Odyssey. Nineteenth- and twentieth-century scholars, such as Michail Jan de Goeje (1836-1909), Enno Littmann (1875-1958), and Richard Hennig (1874-1951) continued the search for the tales' remote origins, each positing dates in the tenth to thirteenth centuries drawing mainly on literary parallels (De Goeje Reizen van Sindebaad, 312; De Goeje La legende de Saint Brendan, 65; Littmann 6: 715-16; Hennig 196-99; Gerhardt 241).Geert Jan Van Gelder and Andras Hamori have pointed to various story motifs found in adapted from stories of the tenth-century author Tanukhi (Van Gelder 421; Hamori 210-15). Jean-Claude Garcin has recently offfered a closer reading of the use of terminology and language in various manuscript recensions as part of his ambitious attempt to fijind a historical context for various tales of the Nights, yet the results are far from conclusive (Garcin 259-80).The fundamental problem is that the textual history of the Voyages of is, as Ulrich Marzolph states in the Encyclopaedia of Islam, largely (Marzolph Sindbad). Recent work by Francesca Bellino on both the extant Arabic and Syriac manuscripts confijirms that there is none predating the seventeenth century (Bellino).This paper, tracing a single motif, may prove important for reconstructing the later travel of the stories before their translation by Galland in the seventeenth century. It follows one hitherto unknown textual route through which one of the voyages traveled.Scholars had long noted that the burial of the living spouse along with the deceased partner described in the fourth voyage of exhibited striking similarities to a story found in the tenth-century collection of Mu?assin b. ?Ali al-Tanukhi. Drawing on a maqama tale from a hitherto unknown and unstudied collection from the sixteenth century, the Maqamat ?Abbasiyya, authored by alSayyid ?Abd al-Ra?im al-?Abbasi (d. 1566), this article proposes that ?Abbasi played an important role in the transformation of a tale found in Tanukhi into a version of the tale similar to that found in the tales translated by Galland.Exploring ?Abbasi's transformation of this tale in detail, I consider whether it was ?Abbasi who set this tale in India while he was resident at the court of Suleiman the Magnifijicent in the years 1534-38. I further suggest that ?Abbasi's Maqama Basriyya may reflect Ottoman elite intellectuals' anxieties over their increasing involvement in the Indian Ocean trade during the mid-1530s and particularly their recent establishment of a Rumi trading colony at Diu in Gujarat in the 1530s (Casale 48). The fijinal section of the paper discusses the tale of Cogia Muzafffer, which appears to be yet another version of ?Abbasi's Maqama Basriyya heard by Galland while he was in Istanbul in 1673, nearly a quarter of a decade before he translated Sindbad.Escaping from the Crypt: Sindbad's Fourth VoyageThe Fourth Voyage of is one of the most dramatic and memorable tales of the cycle. …

Abstract B72: Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01)

Abstract Purpose: Patients with high-risk (HR) neuroblastoma (NBL) have a poor prognosis and new treatment strategies are needed. 131I- Meta-Iodobenzylguanidine (MIBG) therapy alone has a significant antitumor efficacy against NBL. Topotecan (TPT) is a radio-enhancer and can potentiate radiation-induced cytotoxicity and up-regulate the uptake of MIBG in vitro. We designed a clinical study with upfront 131I-MIBG therapy and Topotecan for HR-NBL. We evaluated short term clinical response rate and outcome. Clinical response was scored according to International Neuroblastoma response Criteria (INRC) and Curie score (MIBG) after 2 courses of MIBG/TPT and after induction chemotherapy and HD ASCT. Haematological toxicity and the effect on harvesting/ feasibility performing autologous stem cell transplantation (ASCT) was evaluated. Topoisomerase-1 activity (Topo-1) levels were measured. Methods: Multi-centre, prospective (window phase II) study performed between 2000-2003 in HR NBL patients treated with 2 cycles of upfront 131I-MIBG therapy followed by the addition of TPT 0.7 mg/m2 for 5 days after each course. Thereafter, patients received 4 courses of VECI chemotherapy, followed by surgery and HD ASCT. Results: Sixteen patients (10 male), median age 2, 8 yrs. NMYC amplified 8/14 (57%) and LOH1P in 7/15 (47%). Surgery performed in 12/16 (75%) patients. Clinical response after 2x MIBG/TPT 15/16 (94%, VGPR/ PR/ MR), 1 PD; after 4x VECI 11/16 (69%, CR/ VGPR/ PR/MR), 3 PD, 1 death and 1 unknown. More than 50% reduction in MIBG Curie score after 2x MIBG/ TPT and subsequent 4x VECI courses in most cases. Overall outcome 2/16 currently alive. Long term follow up was limited, possibly related to low intensity induction chemotherapy as used in this study. Harvesting of stem cells in 13/16 patients (79%), mean yield 2, 2 CD34 pos/ kg, 9/16 (56%) underwent HD ASCT. Haematological toxicity was limited, median platelet recovery after HD ASCT was 73 days. Topo-1 activity was measured in 10/16 tumors, increased compared to reference level. Conclusion: Upfront treatment of HR-NBL with MIBG/TPT is feasible and highly effective after 2 courses. The toxicity is limited (haematological). Stem cell harvesting and HD ASCT are manageable. Citation Format: Max M. van Noesel, Kathelijne CJM Kraal, Jan de Kraker, Berthe LF van Eck-Smit, Godelieve AM Tytgat, Huib N. Caron. Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01). [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B72.

Abstract 4634: Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies

Abstract Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are B-cell malignancies with initial high response rate to chemoimmunotherapy, but are largely considered incurable. Ibrutinib (PCI-32765), an oral Bruton's tyrosine kinase inhibitor recently approved to treat MCL, is under development for other B-cell malignancies. We developed a population pharmacokinetic (PK) model for describing data collected to date in clinical trials with ibrutinib. Ibrutinib plasma data were available from 3 clinical trials: 1) a phase 1 dose-escalation study in recurrent B-cell malignancies (doses: 1.25-12.5 mg/kg and 560 mg fixed); 2) a phase 1b/2 dose-finding study in CLL (doses: 420 and 840 mg); 3) an open-label, phase 2, fixed-dose study in MCL (dose: 560 mg). Overall, ≈3477 observations were collected in 245 patients following single and repeated daily dosing on different treatment days. A 2-compartment model with sequential zero to first order absorption and first order elimination was implemented. Analyses were performed with a log-transform-both-sides approach. Additive and exponential models were used to describe residual and inter-individual variability, respectively. The first-order conditional estimation method was implemented using NONMEM v 7.1. A linear model constructed with data collected following single and repeated doses of ibrutinib at different dose levels demonstrated that the PK was dose and time independent. Ibrutinib was rapidly absorbed and was characterized by a high oral plasma clearance (≈1000 L/h with between-subject variability of 21.9%; this, for a dose of 560 mg, would lead to an average steady state concentration of ≈22 ng/mL, ie, ≈50 nM) and a high apparent volume of distribution at steady state (≈10,000 L). Though both values are confounded by absolute bioavailability, these values suggest that ibrutinib clearance and volume are high. The half-lives of distribution and terminal phases were estimated to be <1 h and ≈14 h, respectively. Administration of ibrutinib in fasting state was characterized by a 67% relative bioavailability compared to both meal conditions used in the clinical trials and administration after a high-fat meal. The PK parameters were not found to be significantly different between studies and clinical indications. Body weight and coadministration of antacids had a marginal effect on volume of distribution and duration of absorption processes, respectively. No significant effect of covariates such as age, gender, patient pretreatment, or clinical chemistry data was found. Population parameters and inter-individual variability were estimated with good precision. The model provided satisfactory goodness of fit, individual fittings, and visual predictive checks. In conclusion, the proposed population PK model was able to accommodate the plasma concentration-time profiles of ibrutinib across various trials. Citation Format: Eleonora Marostica, Juthamas Sukbuntherng, David Loury, Jan De Jong, Xavier Woot de Trixhie, An Vermeulen, Giuseppe de Nicolao, Susan O'Brien, John C. Byrd, Ranjana Advani, Jesse McGreivy, Italo Poggesi. Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4634. doi:10.1158/1538-7445.AM2014-4634

Abstract 4637: Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell malignancy treated with chemoimmunotherapy. Such treatment results in high response rates but patients may eventually relapse and require alternate therapies. Ibrutinib (PCI-32765), a recently developed novel treatment, is unique in its mechanism as it inhibits Bruton's tyrosine kinase, a key kinase in the B-cell receptor signaling pathway. It's a Biopharmaceutics Classification Systems (BCS) class 2 compound and is metabolized rapidly by CYP3A. Three studies were conducted. The primary objectives were to assess the pharmacokinetics (PK) of ibrutinib under fed and fasted conditions and to assess the impact of food intake timing. Additionally, the safety and tolerability of ibrutinib were assessed. Study 1 was a randomized, open-label, single-center, single-dose, 4-way crossover study in 44 healthy subjects. Study 2 was a multicenter, randomized, repeated-dose crossover study in 16 patients with relapsed or refractory CLL. The ibrutinib dose was 420 mg in both. Study 3 was an open-label, single-center, sequential study to assess absolute bioavailability of ibrutinib 560 mg in 8 healthy subjects. Ibrutinib was well tolerated in these studies. There were no serious adverse events (AEs) or discontinuations due to an AE. There were no clinically significant changes in laboratory safety parameters, electrocardiograms, or vital signs. Administration of ibrutinib to healthy subjects under fasting conditions resulted in approximately 60% of exposure compared to drug intake either 30 min before or 2 h after a high-fat meal. When ibrutinib was taken 30 min after a meal, drug exposure was comparable to the dosing conditions of either 30 min before or 2 h after the meal. Study 2 revealed that under fed conditions, the maximum concentration was 2.24 times greater and the area under the curve was 1.65 times greater compared to the fasted conditions, but similar to uncontrolled food intake conditions. A similar food effect was observed in study 3, in which a standard meal was consumed starting 30 min after dosing. When corrected for repeated dosing in patients, the PK parameters in healthy subjects and patients were comparable. The observed food effect is most likely the result of a decreased (intestinal and hepatic) first-pass effect, rather than an effect on solubilization. Since ibrutinib is a highly permeable compound, residence time in the gut and liver cells could be reduced when mesenteric and portal vein blood flow is increased under fed conditions, making ibrutinib less available to CYP3A clearance. The effect on bioavailability may outweigh the higher clearance due to liver blood flow. In conclusion, food causes no more than a doubling in ibrutinib systemic exposure. Considering the favorable safety profile, ibrutinib can be administered with or without food. Citation Format: Jan de Jong, Juthamas Sukbuntherng, Donna Skee, Joe Murphy, Susan O'Brien, John C. Byrd, Danelle James, Peter Hellemans, Juhui James Jiao, Vijay Chauhan, Italo Poggesi, Erik Mannaert. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2014-4637

Religious Institutes and Catholic Culture in 19th- and 20th-Century Europe ed. by Urs Altermatt, Jan De Maeyer, and Franziska Metzger (review)

Religious Institutes and Catholic Culture in 19th- and 20th-Century Europe ed. by Urs Altermatt, Jan De Maeyer, and Franziska Metzger (review)

Gem-quality rhodonite from Val Malenco (Central Alps, Italy)

Rhodonite from the Mn-deposit of Monte del Forno is one of the more attractive gemstones, together with andradite and nephrite jade, found in Val Malenco (Central Alps, Italy). A complete characterization of this mineral was provided using classical gemological methods and advanced techniques such as X-ray powder diffraction, EMPA-WDS chemical analyses, Raman and mid-infrared spectroscopy. Rhodonite ranges in color from pink, white-pink to green and pale brown, due to the occurrence of various accessory minerals including tephroite, spessartine, biotite, magnetite, calcite, quartz, and Mn-oxides and hydroxides. From a detailed microprobe study, performed both on thin section and rough samples, the resulted chemical composition scatters from the ideal formula MnSi O 3 , due to the occurrence of other cations, such as Ca, Mg and Fe substituting for Mn. Consistent with results of X-ray powder diffraction and IR and Raman spectroscopy, the particularly low content of Ca in in two points analysis suggests the hypothesis of the occurrence of pyroxmangite, probably as relic phase in a fine intergrowth with rhodonite. Data of rhodonite from the most famous classic deposits of the world (Russia, Japan, USA, Australia, Peru, Brazil and Sweden) are also used for comparison.

Network Alert Management Based on Multi Agent Systems for Surveillance and Supervising Software and Hardware Components

As mobile devices (MD) continue to grow in popularity and functionality, the demand for advanced ubiquitous mobile applications in our daily lives also increases. Modern network security systems endorse monitoring as well as control functions in a remote fashion, thus implementing the pervasive computing paradigm; moreover, the intelligence is now often embedded into modern applications. This work presents an intelligent and a pervasive supervising system for network security based on multi-agent systems (MAS) which detects and classifies events and sends notification to user mobile phones. The proposed platform is formed by two components: The first one consists of a Central Software Component (CSC); the supervisor application that manages devices and evaluates logs and alarms of the supervised components. The second one consists of an Embedded Software Component (ESC) on the MD with an ANDROID OS. The purpose of a network alert management is to inform the user of failures and impending issues in due time so that he can fix them before they adversely affect the operation of the Information System (IS).In our platform, we have implemented agents on ESC using JADE-LEAP android, JADE API on CSC and the communication between these two components is performed using the Secure Socket Layer (SSL) protocol.

Mapping spiritual life: a spatial approach to late medieval spirituality

Esta contribucion tiene como objetivo investigar el uso de los conceptos de lugar, espacio y (restriccion de) movimiento en la educacion espiritual de las mujeres religiosas que vivian en comunidades de la Tercera Orden en la diocesis de Utrecht (Paises Bajos). A traves del estudio de las fuentes institucionales, en particular los estatutos de la Orden Tercera, y los textos literarios escritos y utilizados en los conventos de la Tercera Orden (la Informieringheboeck de Jan de Wael y el Jhesus Collacien), el articulo discutira las supuestas oposiciones binarias �dentro/ fuera� y �seguridad de los conventos/ peligros del mundo� que impregnan el texto de los estatutos y forman la columna vertebral de la ensenanza espiritual de las mujeres enclaustradas.

‘The Netherlands and the Polder Model’ - ‘Nederland en het poldermodel’

With the new textbook Nederland en het poldermodel [The Netherlands and the Polder Model] by Utrecht History Professors Maarten Prak and Jan Luiten van Zanden the polder model may be said to have achieved full academic respectability. Asked to compress 1,000 years of Dutch economic and social history into a single 300-page volume targeted at a popular audience, the authors chose to do so by analysing the country’s ups-anddowns entirely in terms of its peculiar type of organisation, the polder model’s presumed strengths and weaknesses. The BMGN - Low Countries Historical Review editors asked four experts in the social and economic history of the Low Countries, Karel Davids and Marjolein ’t Hart (vu Amsterdam/Huygens ing), Jan de Vries (Berkeley), and Bert De Munck (University of Antwerp) to review it, paying particular attention to what the conceptual approach adds to our understanding of the country’s marked economic fluctuations during the pastmillennium. This introduction is part of the discussion forum 'Nederland en het poldermodel' (Maarten Prak and Jan Luiten van Zanden).

Chinese Domestic Interiors and “Consumer Constraint” in Qing China: Evidence from Yangzhou

AbstractIn works that have profoundly influenced contemporary views of China’s economic growth relative to the Europe’s in the sixteenth to nineteenth centuries, Jan De Vries has concluded that “the East Asian industrious revolution is very much a supply-side phenomenon”, while Kenneth Pomeranz and R. Bin Wong among others have concluded that consumer restraint was a characteristic of eighteenth century society. These views are not supported by economic behaviour in Qing Yangzhou, where middle-brow writings show a marked attention to household décor and a high level of interest in material goods, including imports.

An Industrious Revolution in Norway?

Jan de Vries’ theory of an industrious revolution has received much attention from historians working on economic and social development. Its aim is to unify the contrasting descriptions of the rise of the Industrial Revolution, but the question is how it fits the empirical development. This article tests if the industrious revolution is a fruitful concept to use to describe and explain pre-industrial development in Norway. It concludes that Norwegian pre-industrial economic development resembles an industrious revolution only superficially. On closer examination, it is clear that the consumer aspirations that are central in the industrious revolution theory were not the main driving force behind the economic development that took place in pre-industrial Norway. One must instead see the changes in a wider, transnational perspective.

John Henry Newman: Spiritual Director (1845–1890) by Peter C. Wilcox, S.T.D.

NEWMAN STUDIES JOURNAL 60 1 Newman to Jemima Newman,18 May 1863,in Letters and Diaries of John Henry Newman,vol.20,ed. Charles Stephen Dessain (London:Thomas Nelson and Sons, 1970), 443. 2 Wilcox, introduction to John Henry Newman: Spiritual Director (1845–1890) (Eugene, OR:Wipf and Stock, 2013), xv–xxii, xix. Hereafter cited:Wilcox,“Introduction.”The larger text is hereafter cited:Wilcox, John Henry Newman. BOOK REVIEW John Henry Newman: Spiritual Director (1845–1890). By Peter C.Wilcox,S.T.D., Eugene, Oregon: Pickwick Publications, 2013. Pages: 362. Softcover, $33.60. ISBN: 9781620322048. Peter C. Wilcox’s John Henry Newman: Spiritual Director (1845–1890), achieves a feat both unique and fruitful: through its attentiveness to a particular aspect of Newman’s life, the book casts light on the whole of his mission and work. Wilcox focuses on Newman’s letters, which he shows are a treasure trove of insights on spiritual direction.Wilcox grants that while Newman did not embrace the title of spiritual director, his letters to many people during his Catholic period (1845–1890) demonstrate that he performed that role with rare aplomb and earnestness. In this sense,Wilcox’s book does for Newman what Wendy M.Wright and Joseph F. Power did for Francis de Sales in their ground-breaking Classics of Western Spirituality volume, Francis de Sales, Jane de Chantal: Letters of Spiritual Direction (1988): illuminate the deeper coherence of a theologian’s ideas by examining the practical advice he or she gives to others about how to pray and discern God’s role in one’s life.Wilcox’s book takes seriously Newman’s own words to his sister Jemima in 1863: “[A] man’s life lies in his letters.”1 With Newman’s own maxim as his guide,Wilcox is a masterful study of the underlying logic of Newman’s theological mind. There are two interwoven theses inWilcox’s book.The first is that we learn some fundamental truths about Newman’s own spirituality by examining the advice he gave to others.The second is that these fundamental truths help us see Newman’s remarkable blending of theological reflection and the concerns of practical,everyday life.Together, they present a picture of Newman as a man whose scholarly interest in the Christian past, particularly the writings of the Greek Church Fathers and the doctrinal tradition closely associated with them, was in a close symbiosis with his own sense of vocation and mission in the present. Wilcox notes in his introduction that Newman recognized an important distinction between his published scholarly works and his letters.Whereas his books would be read with close and often malevolent scrutiny, therefore requiring vigilant caution with regard to what he put on the page, in his letters Newman could afford to be more candid and unguarded;2 they show a side of Newman not on display elsewhere.Yet there is more to this distinction. In the letters Newman corresponds with a wide variety of people, not all of them scholars.The copious letters he wrote tell a story about Newman that deepens what we know about him, and that indeed can function as a hermeneutic lens through which to view his private mind. If Newman’s Apologia is the first sustained effort at interpreting his own life, then his letters must also count as an indispensable part of this self-interpretation project.As 61 Wilcox notes,Newman always maintained that it is the whole person who thinks,not just the intellect.3 In his many letters offering advice on prayer and spiritual discernment, Newman demonstrates what he means by his more abstract statements on this point. For example, after reading Wilcox’s book, I will not read An Essay in Aid of a Grammar of Assent the same way as I had before. One conclusion thatWilcox draws from reading Newman’s letters is that the laity and the unique processes they undergo on their own paths to holiness—or nonholiness , as the case may be—were truly central to Newman’s thinking about the Church and his mission in it. That may seem like a trivial conclusion to those accustomed to thinking of Newman as a precursor...