To see the other types of publications on this topic, follow the link: De Bruijn Identity.
Journal articles on the topic 'De Bruijn Identity'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'De Bruijn Identity.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Khoolenjani, Nayereh Bagheri, and Mohammad Hossein Alamatsaz. "A DE BRUIJN'S IDENTITY FOR DEPENDENT RANDOM VARIABLES BASED ON COPULA THEORY." Probability in the Engineering and Informational Sciences 30, no. 1 (October 14, 2015): 125–40. http://dx.doi.org/10.1017/s0269964815000315.
Full textAbstract:
De Bruijn's identity shows a link between two fundamental concepts in information theory: entropy and Fisher information. In the literature, De Bruijn's identity has been stated under the assumption of independence between input signal and an additive noise. However, in the real world, the noise could be highly dependent on the main signal. The main aim of this paper is, firstly, to extend De bruijn's identity for signal-dependent noise channels and, secondly, to study how Stein and heat identities are related to De bruijn's identity. Thus, new versions of De Bruijn's identity are introduced in the case when input signal and additive noise are dependent and are jointly distributed according to Archimedean and Gaussian copulas. It is shown that in this generalized model, the derivatives of the differential entropy can be expressed in terms of a function of Fisher information. Our finding enfolds the conventional De Bruijn's identity as some remarks. Then, the equivalence among the new De Bruijn-type identity, Stein's identity and heat equation identity is established. The paper concludes with an application of the developed results in information theory.
2
Park, Sangwoo, Erchin Serpedin, and Khalid Qaraqe. "New perspectives, extensions and applications of De Bruijn identity." Qatar Foundation Annual Research Forum Proceedings, no. 2012 (October 2012): CSPS3. http://dx.doi.org/10.5339/qfarf.2012.csps3.
Full text
3
Lloyd, E. Keith. "De Bruijn enumeration applied to some genetical problems." Mathematical Proceedings of the Cambridge Philosophical Society 103, no. 2 (March 1988): 277–84. http://dx.doi.org/10.1017/s0305004100064847.
Full textAbstract:
Several authors have considered relationships between individuals specified by the genes which they have in common, where two genes are regarded as the same if and only if they are identical by descent from some common ancestor. In particular Thompson [6] considered n pairs of genes, one pair from each of n individuals, and studied the number Nn of gene identity states, the number Mn, k of such states in which there are exactly k distinct genes and the number Dn of genetically distinct states (see Definitions 2 and 4 below). In this type of work the nature of the genes themselves is of no interest, but only which genes are identical to which, and precise definitions are best given in terms of orbits under group actions. Thompson did use some group theory in her work, but not the full machinery of Redfield-Pólya-de Bruijn enumeration.
4
Valero-Toranzo, Irene, Steeve Zozor, and Jean-Marc Brossier. "Generalization of the de Bruijn Identity to General $\phi$ -Entropies and $\phi$ -Fisher Informations." IEEE Transactions on Information Theory 64, no. 10 (October 2018): 6743–58. http://dx.doi.org/10.1109/tit.2017.2771209.
Full text
5
Zozor, Steeve, and Jean-François Bercher. "ϕ-Informational Measures: Some Results and Interrelations." Entropy 23, no. 7 (July 18, 2021): 911. http://dx.doi.org/10.3390/e23070911.
Full textAbstract:
In this paper, we focus on extended informational measures based on a convex function ϕ: entropies, extended Fisher information, and generalized moments. Both the generalization of the Fisher information and the moments rely on the definition of an escort distribution linked to the (entropic) functional ϕ. We revisit the usual maximum entropy principle—more precisely its inverse problem, starting from the distribution and constraints, which leads to the introduction of state-dependent ϕ-entropies. Then, we examine interrelations between the extended informational measures and generalize relationships such the Cramér–Rao inequality and the de Bruijn identity in this broader context. In this particular framework, the maximum entropy distributions play a central role. Of course, all the results derived in the paper include the usual ones as special cases.
6
Jizba, Petr, Jacob Dunningham, and Martin Prokš. "From Rényi Entropy Power to Information Scan of Quantum States." Entropy 23, no. 3 (March 12, 2021): 334. http://dx.doi.org/10.3390/e23030334.
Full textAbstract:
In this paper, we generalize the notion of Shannon’s entropy power to the Rényi-entropy setting. With this, we propose generalizations of the de Bruijn identity, isoperimetric inequality, or Stam inequality. This framework not only allows for finding new estimation inequalities, but it also provides a convenient technical framework for the derivation of a one-parameter family of Rényi-entropy-power-based quantum-mechanical uncertainty relations. To illustrate the usefulness of the Rényi entropy power obtained, we show how the information probability distribution associated with a quantum state can be reconstructed in a process that is akin to quantum-state tomography. We illustrate the inner workings of this with the so-called “cat states”, which are of fundamental interest and practical use in schemes such as quantum metrology. Salient issues, including the extension of the notion of entropy power to Tsallis entropy and ensuing implications in estimation theory, are also briefly discussed.
7
Dubach, Guillaume. "Symmetries of the quaternionic Ginibre ensemble." Random Matrices: Theory and Applications 10, no. 01 (January 10, 2020): 2150013. http://dx.doi.org/10.1142/s2010326321500131.
Full textAbstract:
We establish a few properties of eigenvalues and eigenvectors of the quaternionic Ginibre ensemble (QGE), analogous to what is known in the complex Ginibre case (see [7, 11, 14]). We first recover a version of Kostlan’s theorem that was already at the heart of an argument by Rider [1], namely, that the set of the squared radii of the eigenvalues is distributed as a set of independent gamma variables. Our proof technique uses the De Bruijn identity and properties of Pfaffians; it also allows to prove that the high powers of these eigenvalues are independent. These results extend to any potential beyond the Gaussian case, as long as radial symmetry holds; this includes for instance truncations of quaternionic unitary matrices, products of quaternionic Ginibre matrices, and the quaternionic spherical ensemble. We then study the eigenvectors of quaternionic Ginibre matrices. Angles between eigenvectors and the matrix of overlaps both exhibit some specific features that can be compared to the complex case. In particular, we compute the distribution and the limit of the diagonal overlap associated to an eigenvalue that is conditioned to be at the origin. This complements a recent study of overlaps in quaternionic ensembles by Akemann, Förster and Kieburg [1, 2].
8
KUNDETI, VAMSI, SANGUTHEVAR RAJASEKARAN, and HEIU DINH. "AN EFFICIENT ALGORITHM FOR CHINESE POSTMAN WALK ON BI-DIRECTED DE BRUIJN GRAPHS." Discrete Mathematics, Algorithms and Applications 04, no. 02 (June 2012): 1250019. http://dx.doi.org/10.1142/s179383091250019x.
Full textAbstract:
Sequence assembly from short reads is an important problem in biology. It is known that solving the sequence assembly problem exactly on a bi-directed de Bruijn graph or a string graph is intractable. However, finding a shortest double stranded DNA string (SDDNA) containing all the k-long words in the reads seems to be a good heuristic to get close to the original genome. This problem is equivalent to finding a cyclic Chinese Postman (CP) walk on the underlying unweighted bi-directed de Bruijn graph built from the reads. The Chinese Postman walk Problem (CPP) is solved by reducing it to a general bi-directed flow on this graph which runs in O(|E|2 log 2(|V|)) time. In this paper we show that the cyclic CPP on bi-directed graphs can be solved without reducing it to bi-directed flow. We present a Θ(p(|V| + |E|) log (|V|) + (d max p)3) time algorithm to solve the cyclic CPP on a weighted bi-directed de Bruijn graph, where p = max {|{v|d in (v) - d out (v) > 0}|, |{v|d in (v) - d out (v) < 0}|} and d max = max {|d in (v) - d out (v)}. Our algorithm performs asymptotically better than the bi-directed flow algorithm when the number of imbalanced nodes p is much less than the nodes in the bi-directed graph. From our experimental results on various datasets, we have noticed that the value of p/|V| lies between 0.08% and 0.13% with 95% probability. Many practical bi-directed de Bruijn graphs do not have cyclic CP walks. In such cases it is not clear how the bi-directed flow can be useful in identifying contigs. Our algorithm can handle such situations and identify maximal bi-directed sub-graphs that have CP walks. A Θ(p(|V| + |E|)) time heuristic algorithm based on these ideas has been implemented for the SDDNA problem. This algorithm was tested on short reads from a plant genome and achieves an approximation ratio of at most 1.0134. We also present a Θ((|V| + |E|) log (V)) time algorithm for the single source shortest path problem on bi-directed de Bruijn graphs, which may be of independent interest.
9
Khoolenjani, Nayereh Bagheri, and Mohammad Hossein Alamatsaz. "Extension of de Bruijn's identity to dependent non-Gaussian noise channels." Journal of Applied Probability 53, no. 2 (June 2016): 360–68. http://dx.doi.org/10.1017/jpr.2016.5.
Full textAbstract:
Abstract De Bruijn's identity relates two important concepts in information theory: Fisher information and differential entropy. Unlike the common practice in the literature, in this paper we consider general additive non-Gaussian noise channels where more realistically, the input signal and additive noise are not independently distributed. It is shown that, for general dependent signal and noise, the first derivative of the differential entropy is directly related to the conditional mean estimate of the input. Then, by using Gaussian and Farlie–Gumbel–Morgenstern copulas, special versions of the result are given in the respective case of additive normally distributed noise. The previous result on independent Gaussian noise channels is included as a special case. Illustrative examples are also provided.
10
Zeng, Xiaohua, and Samuel Kaplan. "TspO as a Modulator of the Repressor/Antirepressor (PpsR/AppA) Regulatory System in Rhodobacter sphaeroides 2.4.1." Journal of Bacteriology 183, no. 21 (November 1, 2001): 6355–64. http://dx.doi.org/10.1128/jb.183.21.6355-6364.2001.
Full textAbstract:
ABSTRACT The TspO outer membrane protein of Rhodobacter sphaeroides has been shown to be involved in controlling the transcription of a number of genes which encode enzymes involved in photopigment biosynthesis and the puc operon. The display of regulated genes appears identical to those genes encompassing the PpsR/AppA repressor/antirepressor regulon, although the effect of TspO is modest relative to that of PpsR/AppA. To directly address the hypothesis that TspO is effective through the PpsR/AppA system, we constructed mutant strains with mutations in bothtspO and appA. In all cases, the phenotypes examined resembled those of the appA lesion by itself, leading us to conclude that TspO works through or modulates the PpsR/AppA system and acts upstream of the site of action of these regulatory proteins. In earlier publications, we had suggested that TspO is involved in the efflux of a certain intermediate(s) of the porphyrin biosynthesis pathway and that transcriptional regulation of target gene expression could be explained by the accumulation of a coactivator of AppA function. Although the data reported here do not precisely identify this coactivator, they lend support to this hypothesis. We discuss the importance of this form of gene control as the result of the recent extension of the TspO system toSinorhizobium meliloti, as described by Davey and de Bruijn (M. E. Davey and F. J. de Bruijn, Appl. Environ. Microbiol. 66:5353–5359, 2000). It is therefore possible that this system constitutes a more widely, although not universally, demonstrated form of gene regulation.
11
Zhang, Mengyun, Changying Li, Fumiomi Takeda, and Fuzeng Yang. "Detection of Internally Bruised Blueberries Using Hyperspectral Transmittance Imaging." Transactions of the ASABE 60, no. 5 (2017): 1489–502. http://dx.doi.org/10.13031/trans.12197.
Full textAbstract:
Abstract. Internal bruise damage that occurs in blueberry fruit during harvest operations and postharvest handling lowers the overall quality and causes significant economic losses. The main goal of this study was to nondestructively detect internal bruises in blueberries after mechanical damage using hyperspectral transmittance imaging. A total of 600 hand-harvested blueberries were divided into 20 groups of four storage times (30 min, 3 h, 12 h, and 24 h), two storage temperatures (22°C and 4°C), and three treatments (stem bruise, equator bruise, and control). A near-infrared hyperspectral imaging system was used to acquire transmittance images from 970 to 1400 nm with 5 nm bandwidth. Images were acquired from three orientations (calyx-up, stem-up, and equator-up) for fruit in the control and stem bruise groups and from four orientations (calyx-up, stem-up, equator-up, and equator-down) in the equator bruise groups. Immediately after imaging, the fruit samples were sliced, and the sliced surfaces were photographed. The color images of sliced fruit were used as references. By comparing with the reference color images, the profiles of spatial and spectral intensities were evaluated to observe the effect of orientation and help extract regions of interest (ROIs) of bruised and healthy tissues. A support vector machine (SVM) classifier was trained and tested to classify pixels of bruised and healthy tissues. Classification maps were produced, and the bruise ratio was calculated to identify bruised blueberries (bruise ratio >25%). The average accuracy of blueberry identification was 94.5% with the stem-up orientation. The results indicate that detecting bruised blueberries as soon as 30 min after mechanical damage is feasible using hyperspectral transmittance imaging. Keywords: Blueberry, Bruise detection, Classification, Hyperspectral imagery, Transmittance mode.
12
Colmenarejo, Laura, Joscha Diehl, and Miruna-Ştefana Sorea. "A quadratic identity in the shuffle algebra and an alternative proof for de Bruijn’s formula." European Journal of Combinatorics 99 (January 2022): 103406. http://dx.doi.org/10.1016/j.ejc.2021.103406.
Full text
13
Kamilya, Supreeti, and Sukanta Das. "A Study of Chaos in Cellular Automata." International Journal of Bifurcation and Chaos 28, no. 03 (March 2018): 1830008. http://dx.doi.org/10.1142/s0218127418300082.
Full textAbstract:
This paper presents a study of chaos in one-dimensional cellular automata (CAs). The communication of information from one part of the system to another has been taken into consideration in this study. This communication is formalized as a binary relation over the set of cells. It is shown that this relation is an equivalence relation and all the cells form a single equivalence class when the cellular automaton (CA) is chaotic. However, the communication between two cells is sometimes blocked in some CAs by a subconfiguration which appears in between the cells during evolution. This blocking of communication by a subconfiguration has been analyzed in this paper with the help of de Bruijn graph. We identify two types of blocking — full and partial. Finally a parameter has been developed for the CAs. We show that the proposed parameter performs better than the existing parameters.
14
Novaretti, João V., Jason J. Shin, Marcio Albers, Monique C. Chambers, Moises Cohen, Volker Musahl, and Freddie H. Fu. "Bone Bruise Patterns in Skeletally Immature Patients With Anterior Cruciate Ligament Injury: Shock-Absorbing Function of the Physis." American Journal of Sports Medicine 46, no. 9 (June 8, 2018): 2128–32. http://dx.doi.org/10.1177/0363546518777247.
Full textAbstract:
Background: Bone bruises are frequently found on magnetic resonance imaging (MRI) after anterior cruciate ligament (ACL) injury and have been related to the force associated with the trauma. Yet, little is known about the bone bruise distribution pattern of skeletally immature (SI) patients, as the presence of an open physis may play a role in energy dissipation given its unique structure. Purpose: To describe and compare the location and distribution of tibial and femoral bone bruises, observed on MRI, between 2 groups of ACL-injured knees: the first group with an open physis and the second with a closed physis. Additionally, based on the bone bruise distribution pattern, the secondary aim of the study was to propose a new classification of bone bruise in SI patients. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A retrospective review was conducted to identify all cases of primary ACL tears in patients ≤16 years old, with MRI within 6 weeks of injury between January 2012 and December 2016. Overall, 106 patients were identified: 53 with open physis (skeletally immature [SI] group) and 53 with closed physis as control (skeletally mature [SM] group). MRI scans were reviewed to assess for the presence and location of bone bruises. Longitudinal bone bruise distribution was described as epiphyseal and metaphyseal in both femur and tibia. The proposed classification for tibia and femur has 2 parts: the location of the bone bruise in the (I) lateral, (II) medial, or (III) medial and lateral parts of the bone; and if the bone bruise (a) does not or (b) does cross the physis. For the tibia, if the bone bruise is also present in the central portion, a letter C is added. Results: The SI group had significantly fewer bone bruises cross the physis and extend into the metaphysis than did the SM group for both the tibia (25% vs 85%, respectively; P < .0001) and the femur (4% vs 42%; P < .0001). The most common patterns observed in the SI group were type IIICa in the tibia (medial/lateral and central, not extending into the metaphysis: 42%) and type Ia in the femur (lateral, not extending into the metaphysis: 59%). Conclusion: The data from this study shows that patients with an open physis at the occurrence of an acute ACL rupture have unique bone bruise patterns as compared with those with a closed physis. In the SI patients, the bone bruise pattern is significantly less frequently observed in the tibial and femoral metaphysis.
15
Kastner, Julie Derges. "Healing bruises: Identity tensions in a beginning teacher’s use of formal and informal music learning." Research Studies in Music Education 42, no. 1 (July 23, 2018): 3–18. http://dx.doi.org/10.1177/1321103x18774374.
Full textAbstract:
The purpose of this narrative case study was to describe the developing teacher identity of Nicole Downing, a first-year teacher in the US, in her use of both formal and informal learning processes. As music education continues embracing approaches like informal music learning, it should also reflect on the voices of teachers in the field. Data collection included interviews, observations, and participant writings. Findings revealed that Nicole (a) questioned and eventually accepted her music teacher identity, (b) exhibited a dualism between her use of formal and informal music learning processes, and (c) broadened her community’s definition of school music. Nicole used the metaphor of a bruise to describe how she believed some in her undergraduate studies would judge her interest in popular music and creative musicianship, but as she became a music teacher she had agency to incorporate the informal learning she valued. Nicole exhibited a duality in her use of formal and informal learning processes, which were not integrated in her teaching. Ultimately, she developed a broadened definition of school music that she believed was beneficial for students but perceived negatively by other music teachers. Music teacher education should support teachers’ diverse identities and continue to explore the teaching strategies used in facilitating informal music learning experiences.
16
Lestari, Novia, Yuwana Yuwana, and Zulman Efendi. "LEVELS OF FRESHNESS AND PHYSICAL DAMAGE IDENTIFICATION OF FISH AVAILABLE FOR COMSUMERS AT PASAR MINGGU MARKET BENGKULU." Jurnal Agroindustri 5, no. 1 (May 29, 2015): 44–56. http://dx.doi.org/10.31186/j.agroind.5.1.44-56.
Full textAbstract:
The purpose of this research was to identify level of freshness of some fishes available at Pasar Minggu Market in Bengkulu City based on SNI 01-2729.1-2006. The research was done by observing the available Sarden (Sadinella spp), Tuna (Thunnus spp), Tongkol (Euthynnus pelamial), Bawal Putih (Pampus argenteus) and Kakap Merah (Lutjanus malabaricus) in the morning (07.00 am), noon (12.00 am) and evening (17.00 am) for their freshness during September to Oktober 2013. Result of the research indicated that all of the observed fishes were fresh in the morning; only Sarden became unfresh at noon, and all of the observed fish has turned to unfresh anymore in the evening. Types of physical damage for Sarden was that its stomach was out and its head was off, for Tuna and Tongkol were bruish, injury, and material in the body of fish; for Bawal and Kakap were bruish and injury.
17
Janda, Elzbieta, Camillo Palmieri, Antonio Pisano, Marilena Pontoriero, Enrico Iaccino, Cristina Falcone, Giuseppe Fiume, et al. "Btk regulation in human and mouse B cells via protein kinase C phosphorylation of IBtkγ." Blood 117, no. 24 (June 16, 2011): 6520–31. http://dx.doi.org/10.1182/blood-2010-09-308080.
Full textAbstract:
Abstract The inhibitor of Bruton tyrosine kinase γ (IBtkγ) is a negative regulator of the Bruton tyrosine kinase (Btk), which plays a major role in B-cell differentiation; however, the mechanisms of IBtkγ-mediated regulation of Btk are unknown. Here we report that B-cell receptor (BCR) triggering caused serine-phosphorylation of IBtkγ at protein kinase C consensus sites and dissociation from Btk. By liquid chromatography and mass-mass spectrometry and functional analysis, we identified IBtkγ-S87 and -S90 as the critical amino acid residues that regulate the IBtkγ binding affinity to Btk. Consistently, the mutants IBtkγ carrying S87A and S90A mutations bound constitutively to Btk and down-regulated Ca2+ fluxes and NF-κB activation on BCR triggering. Accordingly, spleen B cells from Ibtkγ−/− mice showed an increased activation of Btk, as evaluated by Y551-phosphorylation and sustained Ca2+ mobilization on BCR engagement. These findings identify a novel pathway of Btk regulation via protein kinase C phosphorylation of IBtkγ.
18
KITLV, Redactie. "Book Reviews." Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 160, no. 4 (2004): 563–620. http://dx.doi.org/10.1163/22134379-90003725.
Full textAbstract:
-Johann Angerler, Achim Sibeth, Vom Kultobjekt zur Massenware; Kulturhistorische und kunstethnologische Studie zur figürlichen Holzschnitzkunst der Batak in Nordsumatra/Indonesien. Herbolzheim: Centaurus, 2003, 416 pp. [Sozialökonomische Prozesse in Asien und Afrika 8.] -Greg Bankoff, Eva-Lotta E. Hedman ,Philippine politics and society in the twentieth century; Colonial legacies, post colonial trajectories. London: Routledge, 2000, xv + 206 pp. [Politics in Asia Series.], John T. Sidel (eds) -Peter Boomgard, Andrew Dalby, Dangerous tastes; The story of spices. London: British Museum Press, 2002, 184 pp. -Max de Bruijn, G.J. Schutte, Het Indisch Sion; De Gereformeerde kerk onder de Verenigde Oost-Indische Compagnie. Hilversum: Verloren, 2002, 254 pp. [Serta Historica 7.] -Laura M. Calkins, Jacqueline Aquino Siapno, Gender, Islam, nationalism and the state in Aceh; The paradox of power, co-optation and resistance. London: RoutledgeCurzon, 2002, xxi + 240 pp. -H.J.M. Claessen, Deryck Scarr, A history of the Pacific islands; Passages through tropical time. Richmond: Curzon, 2001, xviii + 323 pp. -Matthew Isaac Cohen, Sean Williams, The sound of the ancestral ship; Highland music of West Java. Oxford: Oxford University Press, 2001, xii + 276 pp. -Freek Colombijn, Raymond K.H. Chan ,Development in Southeast Asia; Review and prospects. Aldershot: Ashgate, 2002, xx + 265 pp., Kwan Kwok Leung, Raymond M.H. Ngan (eds) -Heidi Dahles, Shinji Yamashita, Bali and beyond; Explorations in the anthropology of tourism. Translated and with an introduction by J.S. Eades, New York: Berghahn, 2003, xix + 175 pp. [Asian Anthropologies.] -Frank Dhont, Hans Antlöv ,Elections in Indonesia; The New Order and beyond. With contributions by Hans Antlöv, Syamsuddin Haris, Endang Turmudi, Sven Cederroth, Kaarlo Voionmaa. London: RoutledgeCurzon, 2004, xii + 164 pp. [Nordic Institute of Asian Studies Monograph Series 88.], Sven Cederroth (eds) -Frank Dhont, Aris Ananta ,Indonesian electoral behaviour; A statistical perspective. Singapore: Institute of Southeast Asian Studies, 2004, xli + 429 pp. [Indonesia's Population Series 2.], Evi Nurvida Arifin, Leo Suryadinata (eds) -Hans Hägerdal, Arnaud Leveau, Le destin des fils du dragon; L'influence de la communauté chinoise au Viêt Nam et en Thaïlande. Paris: L'Harmattan, Bangkok: Institut de Recherche sur l'Asie de Sud Est Contemporaine, 2003, xii + 88 pp. -Han Bing Siong, A.W.H. Massier, Van recht naar hukum; Indonesische juristen en hun taal, 1915-2000. (Privately published), 2003, xiii + 234 pp. [PhD thesis, Leiden University.] -David Hicks, Andrew Berry, Infinite tropics; An Albert Russel Wallace anthology, with a preface by Stephen Jay Gould. London: Verso, 2002, xviii + 430 pp. -Carool Kersten, J. van Goor, Indische avonturen; Opmerkelijke ontmoetingen met een andere wereld. Den Haag: Sdu Uitgevers, 2000, 294 pp. -Lisa Migo, Robert Martin Dumas, 'Teater Abdulmuluk' in Zuid-Sumatra; Op de drempel van een nieuwe tijdperk. Leiden: Onderzoekschool CNWS, School voor Aziatische, Afrikaanse en Amerindische Studies, 2000, 345 pp. -John N. Miksic, Claude Guillot ,Historie de Barus, Sumatra; Le site de Lobu Tua; II; Étude archéologique et documents. Paris: Association Archipel, 2003, 339 pp. [Cahier d'Archipel 30.], Marie-France Dupoizat, Daniel Perret (eds) -Sandra Niessen, Traude Gavin, Iban ritual textiles. Leiden: KITLV Press, 2003, xi + 356 pp. [Verhandelingen 205.] -Frank Okker, Jan Lechner, Uit de verte; Een jeugd in Indië 1927-1946. Met een nawoord van Gerard Termorshuizen. Leiden: KITLV Uitgeverij, 2004, 151 pp. [Boekerij 'Oost en West'.] -Angela Pashia, William D. Wilder, Journeys of the soul; Anthropological studies of death, burial and reburial practices in Borneo. Phillips ME: Borneo Research Council, 2003, vix + 366 pp. [Borneo Research Council Monograph Series 7.] -Jonathan H. Ping, Huub de Jonge ,Transcending borders; Arabs, politics, trade and Islam in Southeast Asia. Leiden: KITLV Press, 2002, viii + 246 pp. [Proceedings 5.], Nico Kaptein (eds) -Anton Ploeg, William C. Clarke, Remembering Papua New Guinea; An eccentric ethnography. Canberra: Pandanus Books, Research School of Pacific and Asian Studies, Australian National University, 2003, 178 pp. -Nathan Porath, Gerco Kroes, Same hair, different hearts; Semai identity in a Malay context; An analysis of ideas and practices concerning health and illness. Leiden: Research School of Asian, African and Amerindian Studies (CNWS), Universiteit Leiden, 2002, 188 pp. -Guido Sprenger, Grant Evans, Laos; Culture and society. Chiang Mai: Silkworm Books, 1999, xi + 313 pp. -Gerard Termorshuizen, Dik van der Meulen, Multatuli; Leven en werk van Eduard Douwes Dekker. Nijmegen: SUN, 2002, 912 pp. -Paige West, Karl Benediktsson, Harvesting development; The construction of fresh food markets in Papua New Guinea. Copenhagen: Nordic Institute of Asian Studies/Ann Arbor: University of Michigan Press, 2002, xii + 308 pp. -Edwin Wieringa, Amirul Hadi, Islam and state in Sumatra; A study of seventeenth-century Aceh. Leiden: Brill, 2004, xiii + 273 pp. [Islamic History and Civilization, 48.] -Robin Wilson, Pamela J. Stewart ,Remaking the world; Myth, mining and ritual change among the Duna of Papua New Guinea. Washington: Smithsonian Institution Press, 2002, xvi + 219 pp. [Smithsonian Series in Ethnographic Enquiry.], Andrew Strathern (eds)
19
de Bruijne, Ad. "Living with Scripture, Living in a Democracy." European Journal of Theology 28, no. 2 (December 1, 2020): 124–35. http://dx.doi.org/10.5117/ejt2019.2.004.brui.
Full textAbstract:
RésuméLes chrétiens ont souvent fait face à des tensions entre leur identité chrétienne et leur statut de citoyens d’une démocratie. Ces tensions constituent une forme particulière de l’inévitable problème fondamental que rencontrent les chrétiens dans toute société au sein de laquelle ils vivent. À la suite de Saint Augustin, on peut exprimer cela en terme de la difficulté à articuler la double appartenance, à la cité de Dieu d’une part et à la « cité des hommes » de l’autre. En dépit de ces tensions, et en vertu de la providence divine, la participation des chrétiens peut aussi contribuer à des bénédictions temporaires pour la société à laquelle ils appartiennent. L’histoire du monde occidental en fournit bien des exemples, dont fait partie l’émergence même des démocraties. Dans le contexte postchrétien actuel, ces fruits historiques de l’influence chrétienne sont souvent dissociés de leurs racines et deviennent par conséquent instables, ou sont contrecarrés par des difficultés, voire des impasses. Ayant conservé leurs racines, les chrétiens peuvent souvent clarifier les choses et proposer des solutions. La contribution chrétienne peut s’avérer fructueuse, par exemple dans le contexte contemporain de l’opposition entre la version libérale de la démocratie de l’Europe occidentale et la version non libérale de l’Europe de l’Est. L’auteur conclut en mentionnant cinq points devant retenir l’attention concernant la participation de chrétiens à la vie d’une démocratie : il s’agit de rester attaché à l’Église qui constitue la communauté politique du Royaume à venir, de considérer l’identification à un organe politique terrestre comme demeurant secondaire, de promouvoir des activités au bénéfice de la société depuis le sein de l’Église, de tenir compte du fait que les objectifs moraux dans le contexte de la société doivent être différents de ceux que l’on adopte dans le contexte de l’Église, et de demeurer fidèle à un style de vie prophétique par la parole et les actes.SummaryChristians have traditionally experienced tensions between their Christian identity and their citizenship in a democracy. This tension is a special variant of the inevitable underlying classical challenge for Christians in all societies where they live. Following Augustine, this can be expressed as the challenge to combine the dual citizenships of the city of God and the ‘city of man’. Despite such tensions, under God’s providence the participation of Christians can also lead to temporary blessings for their societies. Western history provides many examples of this, the development of democracy being one of them. In the current post-Christian context these historical fruits of Christian influence have often become detached from their roots and therefore become unstable or burdened by difficulties and even deadlocks. Being still connected to that root, Christians can often provide clarification and contribute to solutions. This Christian contribution can be made fruitful, for example, in the contemporary clash between Western European liberal and Eastern European illiberal versions of democracy. The article concludes with five points of attention for Christian participation in a democracy: staying anchored in the Church as the political community of the future kingdom, considering earthly political identifications as secondary, developing public grass roots activities from within the Church, realising that moral aims in the context of society have to be different from those in the context of the Church, and remaining faithful to a prophetic lifestyle in word and deed.ZusammenfassungChristen erleben für gewöhnlich Spannungen zwischen ihrer Identität als Christ und als Staatsbürger in einer Demokratie. Diese Spannung stellt eine besondere Variante der unvermeidlichen klassischen Herausforderung dar, der Christen in jeglicher Gesellschaftsform begegnen. Gemäß Augustinus mag sich dies in der Schwierigkeit ausdrücken, die doppelte Staatsbürgerschaft in der ,,Stadt Gottes“ und der ,,Stadt der Menschen“ miteinander zu vereinen. Trotz derartiger Spannungen kann durch die Vorsehung Gottes auch der Einfluss von Christen zu vorübergehenden Segnungen für ihre Gesellschaft führen. Die westliche Geschichte liefert viele Beispiele hierfür, und die Entwicklung der Demokratie ist nur eines davon. Im gegenwärtigen nachchristlichen Kontext haben sich diese historisch gewachsenen Ergebnisse christlichen Einflusses häufig von ihren Wurzeln gelöst und wurden daher unstabil oder von Schwierigkeiten und sogar Blockaden überfrachtet. Solange Christen immer noch mit diesen Wurzeln verbunden sind, sind sie oftmals in der Lage, für eine Klärung von Situationen zu sorgen und zu Lösungen beizutragen. Dieser christliche Einfluss kann zum Beispiel im gegenwärtigen Konflikt zwischen liberalen westeuropäischen und illiberalen osteuropäischen Formen von Demokratie genutzt werden. Der Artikel schließt mit fünf Punkten, die für den Beitrag von Christen in einer Demokratie zu berücksichtigen sind: Christen bleiben in der Gemeinde als der politischen Gemeinschaft des künftigen Reiches Gottes verhaftet, säkulare politische Zuordnungen werden als sekundär betrachtet, öffentliche Basisaktivitäten werden aus der Gemeinde heraus entwickelt, in der Einsicht, dass sich ethische Zielsetzungen im gesellschaftlichen Kontext von jenen im Gemeindekontext unterscheiden müssen und unter der Voraussetzung, dass Christen einem prophetischen Lebensstil in Wort und Tat treu bleiben.
20
Xiao, Ling, Joe-Elie Salem, Sebastian Clauss, Alan Hanley, Aneesh Bapat, Maarten Hulsmans, Yoshiko Iwamoto, et al. "Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase." Circulation 142, no. 25 (December 22, 2020): 2443–55. http://dx.doi.org/10.1161/circulationaha.120.049210.
Full textAbstract:
Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3–8.7; P <0.0001). Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.
21
Harskamp, Ralf E., Simone C. Laeven, Jelle CL Himmelreich, Wim A. M. Lucassen, and Henk C. P. M. van Weert. "Chest pain in general practice: a systematic review of prediction rules." BMJ Open 9, no. 2 (February 2019): e027081. http://dx.doi.org/10.1136/bmjopen-2018-027081.
Full textAbstract:
ObjectiveTo identify and assess the performance of clinical decision rules (CDR) for chest pain in general practice.DesignSystematic review of diagnostic studies.Data sourcesMedline/Pubmed, Embase/Ovid, CINAHL/EBSCO and Google Scholar up to October 2018.Study selectionStudies that assessed CDRs for intermittent-type chest pain and for rule out of acute coronary syndrome (ACS) applicable in general practice, thus not relying on advanced laboratory, computer or diagnostic testing.Review methodsReviewers identified studies, extracted data and assessed the quality of the evidence (using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2)), independently and in duplicate.ResultsEight studies comprising five CDRs met the inclusion criteria. Three CDRs are designed for rule out of coronary disease in intermittent-type chest pain (Gencer rule, Marburg Heart Score, INTERCHEST), and two for rule out of ACS (Grijseels rule, Bruins Slot rule). Studies that examined the Marburg Heart Score had the highest methodological quality with consistent sensitivity (86%–91%), specificity (61%–81%) and positive (23%–35%) and negative (97%–98%) predictive values (PPV and NPV). The diagnostic performance of Gencer (PPV: 20%–34%, NPV: 95%–99%) and INTERCHEST (PPV: 35%–43%, NPV: 96%–98%) appear comparable, but requires further validation. The Marburg Heart Score was more sensitive in detecting coronary disease than the clinical judgement of the general practitioner. The performance of CDRs that focused on rule out of ACS were: Grijseels rule (sensitivity: 91%, specificity: 37%, PPV: 57%, NPV: 82%) and Bruins Slot (sensitivity: 97%, specificity: 10%, PPV: 23%, NPV: 92%). Compared with clinical judgement, the Bruins Slot rule appeared to be safer than clinical judgement alone, but the study was limited in sample size.ConclusionsIn general practice, there is currently no clinical decision aid that can safely rule out ACS. For intermittent chest pain, several rules exist, of which the Marburg Heart Score has been most extensively tested and appears to outperform clinical judgement alone.
22
Goyal, Manisha, Lysiane Hauben, Hannes Pouseele, Magali Jaillard, Katrien De Bruyne, Alex van Belkum, and Richard Goering. "Retrospective Definition of Clostridioides difficile PCR Ribotypes on the Basis of Whole Genome Polymorphisms: A Proof of Principle Study." Diagnostics 10, no. 12 (December 12, 2020): 1078. http://dx.doi.org/10.3390/diagnostics10121078.
Full textAbstract:
Clostridioides difficile is a cause of health care-associated infections. The epidemiological study of C. difficile infection (CDI) traditionally involves PCR ribotyping. However, ribotyping will be increasingly replaced by whole genome sequencing (WGS). This implies that WGS types need correlation with classical ribotypes (RTs) in order to perform retrospective clinical studies. Here, we selected genomes of hyper-virulent C. difficile strains of RT001, RT017, RT027, RT078, and RT106 to try and identify new discriminatory markers using in silico ribotyping PCR and De Bruijn graph-based Genome Wide Association Studies (DBGWAS). First, in silico ribotyping PCR was performed using reference primer sequences and 30 C. difficile genomes of the five different RTs identified above. Second, discriminatory genomic markers were sought with DBGWAS using a set of 160 independent C. difficile genomes (14 ribotypes). RT-specific genetic polymorphisms were annotated and validated for their specificity and sensitivity against a larger dataset of 2425 C. difficile genomes covering 132 different RTs. In silico PCR ribotyping was unsuccessful due to non-specific or missing theoretical RT PCR fragments. More successfully, DBGWAS discovered a total of 47 new markers (13 in RT017, 12 in RT078, 9 in RT106, 7 in RT027, and 6 in RT001) with minimum q-values of 0 to 7.40 × 10−5, indicating excellent marker selectivity. The specificity and sensitivity of individual markers ranged between 0.92 and 1.0 but increased to 1 by combining two markers, hence providing undisputed RT identification based on a single genome sequence. Markers were scattered throughout the C. difficile genome in intra- and intergenic regions. We propose here a set of new genomic polymorphisms that efficiently identify five hyper-virulent RTs utilizing WGS data only. Further studies need to show whether this initial proof-of-principle observation can be extended to all 600 existing RTs.
23
Giuffre, Liz. "Adapting Idols: Authenticity, Identity and Performance in the Global Television Format. Edited by Koos Zwaan and Joost de Bruin. Farnham: Ashgate, 2012. 237 pp. ISBN 978-1-4094-4169-4." Popular Music 35, no. 1 (November 30, 2015): 143–44. http://dx.doi.org/10.1017/s0261143015000707.
Full text
24
Bornstein, Natan M., Lorraine G. Chadwick, and John W. Norris. "The Value of Carotid Doppler Ultrasound in Asymptomatic Extracranial Arterial Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 15, no. 4 (November 1988): 378–83. http://dx.doi.org/10.1017/s0317167100028080.
Full textAbstract:
ABSTRACT:Carotid Doppler is an accurate, safe and repeatable method of assessing arterial calibre, for distinguishing harmless neck bruits and to identify the stroke prone individual. It is completely non-invasive and can be used serially to monitor progression in carotid stenosis. It is a valuable clinical tool in diagnosis and management in patients at risk of stroke, but has definite limitations, such as in differentiating carotid occlusion from severe stenosis. B-mode imaging, although valuable in identifying arterial anatomy, and detecting plaques, cannot accurately evaluate the degree of stenosis. It is of limited value in identifying plaque hemorrhage and ulceration. Doppler ultrasound technology has advanced rapidly in the last decade, especially in the combination of B-mode imaging and Doppler (Duplex), as well as in evaluating of the intracranial circulation (transcranial Doppler). In the next decade, it may become the new gold standard for evaluating the extracranial and intracranial circulation.
25
Awan, Farrukh T., Othman Al-Sawaf, Kirsten Fischer, and Jennifer A. Woyach. "Current Perspectives on Therapy for Chronic Lymphocytic Leukemia." American Society of Clinical Oncology Educational Book, no. 40 (May 2020): 320–29. http://dx.doi.org/10.1200/edbk_279099.
Full textAbstract:
Therapy for chronic lymphocytic leukemia has improved dramatically over the past decade with the introduction of new targeted therapies and a paradigm shift toward targeted therapies for the majority of patients. Better understanding of prognostic factors has helped tailor therapy for individual patients, and work continues to identify optimal therapy for each patient. When therapy is required, most patients will be treated with targeted therapies, either the Bruton tyrosine kinase (BTK) inhibitors ibrutinib or acalabrutinib or the BCL-2 inhibitor venetoclax in combination with obinutuzumab. Without head-to-head comparisons showing differential efficacy among these options, considerations regarding safety, patient preference, and ability to sequence therapy currently influence treatment decisions. Also, clinical trials investigating combinations of these therapies have the potential to further change the standard of care. In this review, we cover the currently available options for the frontline treatment of chronic lymphocytic leukemia (CLL) and discuss safety considerations and toxicity management with each agent as well as novel combination strategies currently under investigation.
26
DePhillipo, Nicholas N., Mark E. Cinque, Jorge Chahla, Andrew G. Geeslin, Lars Engebretsen, and Robert F. LaPrade. "Incidence and Detection of Meniscal Ramp Lesions on Magnetic Resonance Imaging in Patients With Anterior Cruciate Ligament Reconstruction." American Journal of Sports Medicine 45, no. 10 (May 2, 2017): 2233–37. http://dx.doi.org/10.1177/0363546517704426.
Full textAbstract:
Background: Meniscal ramp lesions have been reported to be present in 9% to 17% of patients undergoing anterior cruciate ligament (ACL) reconstruction. Detection at the time of arthroscopy can be accomplished based on clinical suspicion and careful evaluation. Preoperative assessment via magnetic resonance imaging (MRI) has been reported to have a low sensitivity in identifying meniscal ramp lesions. Purpose: To investigate the incidence of meniscal ramp lesions in patients with ACL tears and the sensitivity of preoperative MRI for the detection of ramp lesions. Study Design: Case series; Level of evidence, 4. Methods: All patients who underwent ACL reconstruction by a single surgeon between 2010 and 2016 were included in this study, and patients with medial meniscal ramp lesions found at the time of arthroscopy were identified. The sensitivity of MRI compared with the gold standard of arthroscopic evaluation was determined by review of the preoperative MRI musculoskeletal radiologist report, mimicking the clinical scenario. The incidence was calculated based on arthroscopic findings, and the potential secondary signs of meniscal ramp tears were evaluated on MRI. Results: In a consecutive series of 301 ACL reconstructions, 50 patients (33 male, 17 female) with a mean age of 29.6 years (range, 14-61 years) were diagnosed with a medial meniscal ramp lesion at arthroscopic evaluation (16.6% incidence). The sensitivity of MRI for ramp lesions was 48% based on the preoperative MRI report. A secondary finding of a posteromedial tibial bone bruise was identified on preoperative MRI in 36 of the 50 patients with ramp lesions in a retrospective MRI review by 2 orthopaedic surgeons. Conclusion: Medial meniscal ramp lesions were present in approximately 17% of 301 patients undergoing ACL reconstruction, and less than one-half were diagnosed on the preoperative MRI. A posteromedial tibial bone bruise was found to be a secondary sign of a ramp lesion in 72% of patients. Increased awareness of this potentially combined injury pattern is necessary, and careful intraoperative evaluation is required to identify all meniscal ramp tears.
27
Nanduri, J., and J. W. Kazura. "Clinical and laboratory aspects of filariasis." Clinical Microbiology Reviews 2, no. 1 (January 1989): 39–50. http://dx.doi.org/10.1128/cmr.2.1.39.
Full textAbstract:
Human filarial infections afflict over 150 million persons worldwide and are major causes of morbidity in many developing countries. Onchocerca volvulus infection is a leading preventable cause of blindness, while bancroftian and brugian filariasis may produce lymphatic obstruction of the genitalia and extremities (elephantiasis). Definitive diagnosis of these helminthic infections currently depends on demonstration of microfilariae in host tissues, i.e., the skin in the case of O. volvulus and the bloodstream in the cases of Wuchereria bancrofti and Brugia malayi. Many investigations are now directed at developing specific and sensitive serum antigen assays that will allow diagnosis of active infection (i.e., presence of adult-stage parasites) in the absence of detectable microfilariae. With respect to the immunology of these parasitic infections, efforts are being directed at elucidating the role of T- and B-cell responses in the development of pathologic lesions and resistance to reinfection. These data as well as molecular biologic approaches to identify and study filarial molecules which are immunogenic are discussed. Finally, since treatment of filariases at present depends on antiparasitic drugs, the clinical indications and dosages of diethylcarbamazine and ivermectin are summarized.
28
Mueller, Helena, Anika Stadtmann, Hugo Van Aken, Emilio Hirsch, Demin Wang, Klaus Ley, and Alexander Zarbock. "Tyrosine kinase Btk regulates E-selectin–mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways." Blood 115, no. 15 (April 15, 2010): 3118–27. http://dx.doi.org/10.1182/blood-2009-11-254185.
Full textAbstract:
Abstract Selectins mediate leukocyte rolling, trigger β2-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)–dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) γ2– and phosphoinositide 3-kinase (PI3K) γ–dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP3), and inducing E-selectin–mediated slow rolling. Inhibition of this signal-transduction pathway diminished Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk−/− and Plcg2−/− mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.
29
Sarangdhar, Mayur, Bruce Aronow, Anil Goud Jegga, Brian Turpin, Erin Haag Breese, and John Peter Perentesis. "Large scale adverse event data mining for targeted therapies development." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 2538. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2538.
Full textAbstract:
2538 Background: Targeted anti-cancer small molecule drugs & immune therapies have had a dramatic impact in improving outcomes & the approach to clinical trials. Increasingly, regulatory approvals are expedited with small studies designed to identify strong efficacy signals. However, this may limit the extent of safety profiling. The use of large scale/big data meta-analyses can identify novel safety & efficacy signals in "real-world" medical settings. Methods: We used AERSMine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 8.6 million patients. We identified patients (n = 732,198) who received either traditional and targeted cancer therapy & identified therapy-specific toxicity patterns. Patients were classified based on exposures: anthracyclines (n = 83,179), platinum (117,993), antimetabolites (93,062), alkylators (81,507), antimicrotubule agents (97,726), HER2 inhibitors (40,040), VEGFis (79,144), VEGF-TKis (90,734), multi TKis (34,457), anaplastic lymphoma Kis (7,635), PI3K-AKT-mTOR inhibitors (33,864), Bruton TKis (9,247), MEKis (4,018), immunomodulatory agents (174,810), proteasome inhibitors (44,681), immune checkpoint inhibitors (20,287). Pharmacovigilance metrics [Relative Risks & safety signals] were used to establish statistical correlation & toxicity signatures were differentiated using the Kolmogorov–Smirnov test. Results: To validate the use of the AERSMine to detect AEs, we focused on cardiotoxicity. It identified classic drug associated AEs (e.g. ventricular dysfunction with anthracyclines, HER2is & VEGFis; VEGFi hypertension & vascular toxicity; multi TKIs vascular events). AERSMine also identified recently reported uncommon toxicities of myositis/myocarditis with immune checkpoint inhibitors. It indicated a higher frequency of myositis/myocarditis with combination immune checkpoint therapy, paralleling industry corporate safety databases. These toxicities were reported at higher frequencies in patients > 65 yrs. Conclusions: AERSMine “big data” analyses provide a sensitive tool to detect potential new patterns of AEs simultaneously across multiple clinical trials & in the real-world setting.
30
Yablonovitch, Arielle, Sante Gnerre, Lesli Ann Kiedrowski, Jennifer Yen, Leo Liu, Elena Helman, Stephen R. Fairclough, Rebecca Nagy, Darya Chudova, and AmirAli Talasaz. "Identification of FGFR2/3 fusions from clinical cfDNA NGS using a de novo fusion caller." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3545. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3545.
Full textAbstract:
3545 Background: FGFR2/ 3 rearrangements are promising therapeutic targets, especially in advanced urothelial cancer (aUC) with FDA-approved erdafitinib. Liquid biopsy is an attractive non-invasive method to identify these fusions, but detection in cfDNA is technically challenging due to low tumor shedding levels, short molecules, and wide variation in gene partners. To address this, we developed an assembly-based fusion detection algorithm to call rearrangements in a de novo fashion without reliance on a fixed partner set and applied it to > 15,000 clinical samples. Methods: A cohort of 15,218 patients with mixed cancer types (including 698 aUC patients, as well as breast, cholangiocarcinoma, colorectal, and gastric), plus 276 healthy control samples were previously tested with Guardant360(R), a clinical 74-gene cfDNA NGS-based assay. The median unique molecule coverage was approximately 3,000 molecules sequenced to 15,000x read depth. Samples were reanalyzed in silico using the novel algorithm: in brief, reads aligned to candidate fusion breakpoints were assembled into de Bruijn graphs. Resulting contigs were aligned to the reference and filters were applied to remove technical artifacts. Results: The majority of FGFR2 (86%) and FGFR3 fusion partners (73%) in the mixed cancer cohort were observed only once, consistent with previous reports (Helsten 2016). FGFR3-TACC3 was the most common fusion, occurring in 72% of FGFR3 fusion-positive patients. In 37% of FGFR2 fusion positive patients, the de novo caller detected partners not previously described. In the aUC cohort, FGFR3 fusions were detected in 3.3% of patients, with 8/10 (80%) partner genes/intergenic regions occurring only once, which is in line with previous reports (Nassar 2018). No fusions were identified in 276 healthy control samples. In the mixed cancer cohort, common mutations co-occurring with FGFR2 fusions were FGFR2 N549K, PIK3CA H1047R, and TP53 R175H (5.6% each); KRAS Q61H was observed in 28% of patients with FGFR3 fusions. Conclusions: FGFR2/ 3 fusion partners detected by a highly specific assembly-based de novo fusion caller were heterogeneous and individually rare, highlighting the importance of a de novo approach. We observed an FGFR3 fusion prevalence in cfDNA from aUC patients that is comparable to previous reports for tissue testing, demonstrating an ability to capture targetable genomic rearrangements with plasma-based NGS in this patient population.
31
Mondal, Satadal, Indranil Sen, Rabi Hembrom, Swagato Roy, Rupam Sinha, Mayur Nair, and Tapas Kumar Mahato. "Epidemiological Analysis of Maxillofacial Injuries in Road Traffic Accidents: A Peripheral Hospital Based Study." Bengal Journal of Otolaryngology and Head Neck Surgery 28, no. 1 (April 30, 2020): 10–16. http://dx.doi.org/10.47210/bjohns.2020.v28i1.20.
Full textAbstract:
Introduction
The aetiology of maxillofacial fractures is greatly influenced by geographic location, socioeconomic status of the cohort, and the period of investigation. The aim of this study is to analyze and identify characteristics of maxillo-facial fractures that took place in and around Midnapore- Kharagpore city of West Bengal and who presented to a peripheral medical college hospital during a period of 1 year.
Materials and Methods
A detailed database analysis was performed based on data collected from the patients of Road Traffic Accidents (RTA) with sustained facial trauma admitted to General Surgery and Otorhinolaryngology ward of a peripheral medical college hospital. Detailed clinical examination as well as radiological data was collected.
Results
The highest frequency of maxillo-facial injury due to RTA was among the young adults 18-40 years. Most common type of injury encountered is abrasion (44%) followed by bruise and closed fracture. Mandible is the most common bone to get fractured and most common type of Le fort type is Type II. Significant number of patients having RTA were young adults under the influence of alcohol riding in two-wheeler .
ConclusionWith the increasing incidence of RTA awareness must be created concerning safety rules and more policies need to be addressed.
32
Afandi, Dedi, Mohammad T. Indrayana, Iriandanu Nugraha, and Dinda Danisha. "Prevalence and pattern of domestic violence at the Center for Forensic Medical Services in Pekanbaru, Indonesia." Medical Journal of Indonesia 26, no. 2 (August 18, 2017): 97–101. http://dx.doi.org/10.13181/mji.v26i2.1865.
Full textAbstract:
Background: Domestic violence (DV) is still a significant public health problem, especially in women’s health. Few studies have reported the prevalence and domestic violence in Indonesia. The aim of this study was to identify the prevalence, type of violence, and forensic examination on domestic violence victims in emergency departments.Methods: This study was a retrospective analysis of domestic violence victims observed in the Emergency Department at the Bhayangkara Hospital, Pekanbaru, Indonesia, between 2010 and 2014. The determinations of DV cases are based on the medico-legal reports (visum et repertum) and the police’s official inquiry letters.Results: Out of 6,876 medico-legal injury reports of living victims were reviewed, and 755 (10,9%) cases were DV. The majority of victims in DV were women (93.8%) with childbearing age group as the highest frequency (77.9%). Most of the DV victims were housewives (67.0%). Moreover, physical assault was the most common DV types (98.7%). Bruise was the predominant type of wound among the DV victims (76.2%), and almost half of the victims had abrasions (48.1%). Head and limbs were the predominant sites of wound. Blunt injury was found in more than three-quarters of the victims (88.5%).Conclusion: The prevalence of domestic violence was high among living victims in the emergency department, with women as the majority of victims.
33
Huet, Sarah, and Gilles Salles. "Potential of Circulating Tumor DNA for the Management of Patients With Lymphoma." JCO Oncology Practice 16, no. 9 (September 2020): 561–68. http://dx.doi.org/10.1200/jop.19.00691.
Full textAbstract:
The characterization of circulating tumor-derived DNA (ctDNA) has recently emerged in the field of oncology as a powerful method to identify tumor-specific genetic aberrations using peripheral blood testing. Several technical precautions are needed at the pre-analytic stage (given the short half-life of free nucleic acids in plasma), and numerous techniques—with different sensitivities—are available to identify these molecular aberrations, ranging from the detection of single point mutations to extended genetic screening panels. Although a “liquid biopsy” cannot be substituted for the pathological examination of tissue specimens for diagnostic purposes, it can sometimes complement pathology results or serve as a proxy approach for particular lymphoma presentations where biopsies are sometimes difficult to perform. Moreover, ctDNA testing can characterize, at diagnosis or during treatment, mutations that may contribute to the choice of an optimal targeted therapy (such as Bruton tyrosine kinase or EZH2 inhibitors) or detect the emergence of resistance to those therapies. High levels of ctDNA before treatment appear to be correlated with advanced disease stages and prognosis in diffuse large B-cell and follicular lymphomas. Real-time follow-up of ctDNA levels during therapy in several lymphoma subtypes (diffuse large B-cell and Hodgkin lymphomas) has been explored: preliminary studies have demonstrated that this monitoring technique can predict clinical outcomes (end of treatment response and risk of progression after treatment completion) and that this approach may complement the information provided by metabolic imaging assessments. Technical standardization and careful prospective evaluation of the role of ctDNA monitoring in clinical studies represent current important challenges to allowing its application in routine practice.
34
Ormsby, Tereza, Eva Schlecker, Janina Ferdin, Anja Sibylle Tessarz, Pavla Angelisová, Afitap Derya Köprülü, Michael Borte, et al. "Btk is a positive regulator in the TREM-1/DAP12 signaling pathway." Blood 118, no. 4 (July 28, 2011): 936–45. http://dx.doi.org/10.1182/blood-2010-11-317016.
Full textAbstract:
Abstract The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca2+ mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1–induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk−/− mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1–mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.
35
Kemp, Alison M., Frank Dunstan, Diane Nuttall, M. Hamilton, Peter Collins, and Sabine Maguire. "Patterns of bruising in preschool children—a longitudinal study." Archives of Disease in Childhood 100, no. 5 (January 14, 2015): 426–31. http://dx.doi.org/10.1136/archdischild-2014-307120.
Full textAbstract:
IntroductionThis study aims to identify the prevalence and pattern of bruises in preschool children over time, and explore influential variablesMethodsProspective longitudinal study of children (<6 years) where bruises were recorded on a body chart, weekly for up to 12 weeks. The number and location of bruises were analysed according to development. Longitudinal analysis was performed using multilevel modelling.Results3523 bruises recorded from 2570 data collections from 328 children (mean age 19 months); 6.7% of 1010 collections from premobile children had at least one bruise (2.2% of babies who could not roll over and 9.8% in those who could), compared with 45.6% of 478 early mobile and 78.8% of 1082 walking child collections. The most common site affected in all groups was below the knees, followed by ‘facial T’ and head in premobile and early mobile. The ears, neck, buttocks, genitalia and hands were rarely bruised (<1% of all collections). None of gender, season or the level of social deprivation significantly influenced bruising patterns, although having a sibling increased the mean number of bruises. There was considerable variation in the number of bruises recorded between different children which increased with developmental stage and was greater than the variation between numbers of bruises in collections from the same child over time.ConclusionsThese data should help clinicians understand the patterns of ‘everyday bruising’ and recognise children who have an unusual numbers or distribution of bruises who may need assessment for physical abuse or bleeding disorders.
36
Jeong, Byung Yong. "Prevalence of occupational accidents and factors associated with deaths and disabilities in the shipbuilding industry: Comparisons of novice and skilled workers." Work 69, no. 3 (July 16, 2021): 997–1005. http://dx.doi.org/10.3233/wor-213530.
Full textAbstract:
BACKGROUND: The shipbuilding industry has various risks such as slipping, falling, mechanical, chemical, and confined space work. OBJECTIVE: The purpose of this study is to compare the characteristics of the occupational accidents between novice and skilled workers in the shipbuilding industry and to analyze factors affecting death and disability accidents. METHODS: From the national work-related compensation data of South Korea, an experimental design was established to analyze a population of occupational injuries related to workers working in the shipbuilding industry. This study compares accident characteristics of 2,069 injuries registered as work-related accidents. Also, logistic regression analysis is performed to identify the factors affecting death and disability accidents. RESULTS: The prevalence of occupational accidents caused by novices was high in older workers, female workers, foreign workers, irregular workers, or companies with less than 100 employees. The proportion of source of accident by novices was high in ‘manhole,’‘ladder,’ and ‘scaffold,’ while the prevalence of accident type was high in ‘fall,’ ‘cut/bruise,’ and ‘struck by.’ According to logistic regression analysis, if the face was injured, the possibility of being death or disability was higher than that of other parts of the body. Also, if the rupture caused the injury, the possibility of being death or disability was higher than the different types of injury. CONCLUSIONS: The results of this study are expected to be useful as basic data for the prevention of accidents of novice and death/disabilities in the shipbuilding industry.
37
Farzana Islam, Nashid Tabassum Khan, Sohel Mahmud, Farhana Shahid, Mahbub Alam Mondal, and Shanjida Munmun. "Road traffic accidents, the leading cause of death: A retrospective study." Z H Sikder Women’s Medical College Journal 3, Number 2 (June 1, 2021): 26–29. http://dx.doi.org/10.47648/zhswmcj.2021.v0302.06.
Full textAbstract:
Road traffic accidents (RTAs) has spiked over the past few years and has become a major public health concern in Bangladesh. Globally, RTA causes 1.35 million deaths annually. The consequences of road traffic accident not only affect the victim’s physical, psychological and financial hardship, but also has fatal impact on the functioning of the whole family. The objective of this study was to evaluate the present situation of RTA in Dhaka city, to find out the pattern of injuries, to identify the causes, frequency, socio- demographic characteristics of the victims and to identify the measures to minimize the incidence of RTAs. This retrospective study was conducted in the department of Forensic Medicine & Toxicology of Dhaka Medical College during January 2019 to December 2019. A total of 154 medico-legal cases of road traffic accidents were brought to the mortuary of Dhaka Medical College from 23 police stations and 1 railway Thana. Data was collected from inquest report, Challan and postmortem reports from the department of Forensic Medicine and Toxicology, Dhaka Medical College. This study shows that a total of 154 post mortems of RTA cases were conducted at DMC morgue during January 2019 to December 2019. Greater number of the accidents occurred during June 28 (18.18%) and August 25 (16.23%). Among the victims, 114 (74.03%) were male and 40 (25.97%)were female. Most of fatality was among the age group 22 to 27 years (48, 31.17%) followed by 28 to 33 years age group (32, 20.78%). By relidion, Muslims were 130 (84.41%), followed by Hindus (19, 12.34 %), and Christians (05, 3.25 %). Considering the injury patterns, all victims had multiple abrasion and bruise 154 (100%), fracture ribs 28 (18.18%), fracture hipbones 26(16.88 %), fracture skull bones 17 (11.04%), head injury 24 (15.58%) and intracranial haemorrhages 24 (15.58%). Road traffic accidents can be minimized by creating public awareness among all road users about traffic signals and traffic safety rules as far as private users of vehicles are concerned.
38
Mutlu, Serhat, Harun Mutlu, Baran Kömür, Olcay Guler, Bulent Yucel, and Atilla Parmaksızoğlu. "Magnetic Resonance Imaging-Based Diagnosis of Occult Osseous Injuries in Traumatic Knees." Open Orthopaedics Journal 9, no. 1 (March 31, 2015): 84–88. http://dx.doi.org/10.2174/1874325001509010084.
Full textAbstract:
Background : Occult osseous knee injuries, such as bone bruises, can produce persistent pain and functional loss. Although bone bruises cannot be identified through direct examination or traditional radiographs, magnetic resonance imaging (MRI) has emerged as an effective diagnostic method. Nevertheless, the natural history of these injuries remains to be fully defined. Therefore, we used MRI to detect and follow bone bruise injuries secondary to knee trauma. Methods : We retrospectively reviewed knee MRIs from patients with bone bruising caused by trauma. Occult injuries were initially identified by MRI and subsequently rescanned for follow-up at 3 and 9 months. All patients underwent physical examinations, direct radiological imaging, and MRI. Results : Although direct radiographs showed no abnormalities, we used MRI to identify a total of 22 patients (age range: 19–42 years; mean: 28 years) with bone bruising. After 3 months, injuries remained detectable in 68.2% of the subjects, whereas 18.2% displayed bone bruising after 9 months. The majority of Type I lesions resolved spontaneously, whereas 80% of Type II injuries remained following 3 months, and 30% persisted at 9 months. Ligament and meniscal lesions were observed in 63.6% of patients with bone bruising and appeared to hinder recovery. Conclusion : Bone bruises generally resolved within 3 to 9 months in subjects with no soft tissue lesions and minor trauma. However, ligament and meniscal lesions were observed in the majority of patients, and these individuals required longer treatment and recuperation. Overall, these findings can contribute to improving the management of occult osseous knee injuries.
39
Zhao, Zeying, Hanwen Zhou, Zhongnan Nie, Xuekui Wang, Biaobiao Luo, Zhijie Yi, Xinghua Li, Xuebo Hu, and Tewu Yang. "Appropriate Reference Genes for RT-qPCR Normalization in Various Organs of Anemone flaccida Fr. Schmidt at Different Growing Stages." Genes 12, no. 3 (March 23, 2021): 459. http://dx.doi.org/10.3390/genes12030459.
Full textAbstract:
Anemone flaccida Fr. Schmidt is a traditional medicinal herb in southwestern China and has multiple pharmacological effects on bruise injuries and rheumatoid arthritis (RA). A new drug with a good curative effect on RA has recently been developed from the extract of A. flaccida rhizomes, of which the main medicinal ingredients are triterpenoid saponins. Due to excessive exploitation, the wild population has been scarce and endangered in a few of its natural habitats and research on the cultivation of the plant commenced. Studies on the gene expressions related to the biosynthesis of triterpenoid saponins are not only helpful for understanding the effects of environmental factors on the medicinal ingredient accumulations but also necessary for monitoring the herb quality of the cultivated plants. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) as a sensitive and powerful technique has been widely used to detect gene expression across tissues in plants at different stages; however, its accuracy and reliability depend largely on the reference gene selection. In this study, the expressions of 10 candidate reference genes were evaluated in various organs of the wild and cultivated plants at different stages, using the algorithms of geNorm, NormFinder and BestKeeper, respectively. The purpose of this study was to identify the suitable reference genes for RT-qPCR detection in A. flaccida. The results showed that two reference genes were sufficient for RT-qPCR data normalization in A. flaccida. PUBQ and ETIF1a can be used as suitable reference genes in most organs at various stages because of their expression stabilitywhereas the PUBQ and EF1Α genes were desirable in the rhizomes of the plant at the vegetative stage.
40
Sharma, Sonali, Gabriela Mladonicka Pavlasova, Vaclav Seda, Katerina Amruz Cerna, Eva Vojackova, Daniel Filip, Laura Ondrisova, et al. "miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors." Blood 137, no. 18 (May 6, 2021): 2481–94. http://dx.doi.org/10.1182/blood.2020005627.
Full textAbstract:
Abstract B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor–associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40–NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29–TRAF4–CD40 signaling axis modulated by BCR activity.
41
Kakodkar, Pramath, Sanket More, Kinga András, Nikos Papakonstantinou, Sharon Kelly, Mohammad Adib Makrooni, Csaba Ortutay, and Eva Szegezdi. "Aspartic Aminopeptidase Is a Novel Biomarker of Aggressive Chronic Lymphocytic Leukemia." Cancers 12, no. 7 (July 12, 2020): 1876. http://dx.doi.org/10.3390/cancers12071876.
Full textAbstract:
Treatment of chronic lymphocytic leukemia has advanced substantially as our understanding of the kinase signal transduction pathways driven by the B cell receptor (BcR) has developed. Particularly, understanding the role of Bruton tyrosine kinase and phosphatidyl inositol 3 kinase delta in driving prosurvival signal transduction in chronic lymphocytic leukemia (CLL) cells and their targeting with pharmacological inhibitors (ibrutinib and idelalisib, respectively) has improved patient outcomes significantly. The kinase signaling pathway induced by the BcR is highly complex and has multiple interconnecting branches mediated by tyrosine and serine/threonine kinases activated downstream of the BcR. There is a high level of redundancy in the biological responses, with several BcR-signaling kinases driving nuclear factor kappa B activation or inducing antiapoptotic Bcl-2 genes. Accordingly, common gene targets of BcR-signaling kinases may serve as biomarkers indicating enhanced BCR-signaling and aggressive disease progression. This study used a gene expression correlation analysis of malignant B cell lines and primary CLL cells to identify genes whose expression correlated with BCR-signaling kinases overexpressed and/or overactivated in CLL, namely: AKT1, AKT2, BTK, MAPK1, MAPK3, PI3KCD and ZAP70. The analysis identified a 32-gene signature with a strong prognostic potential and DNPEP, the gene coding for aspartic aminopeptidase, as a predictor of aggressive CLL. DNPEP gene expression correlated with MAPK3, PI3KCD, and ZAP70 expression and, in the primary CLL test dataset, showed a strong prognostic potential. The inhibition of DNPEP with a pharmacological inhibitor enhanced the cytotoxic potential of idelalisib and ibrutinib, indicating a biological functionality of DNPEP in CLL. DNPEP, as an aminopeptidase, contributes to the maintenance of the free amino acid pool in CLL cells found to be an essential process for the survival of many cancer cell types, and thus, these results warrant further research into the exploitation of aminopeptidase inhibitors in the treatment of drug-resistant CLL.
42
Bhargava, Pavan, Sol Kim, Arthur A. Reyes, Roland Grenningloh, Ursula Boschert, Martina Absinta, Carlos Pardo, Peter Van Zijl, Jiangyang Zhang, and Peter A. Calabresi. "Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition." Brain 144, no. 5 (March 16, 2021): 1396–408. http://dx.doi.org/10.1093/brain/awab045.
Full textAbstract:
Abstract Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139–151) and complete Freund’s adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.
43
Tham, Kenneth, Stacy Prelewicz, Sara deHoll, Deborah Stephens, and Carlos A. Gomez. "1087. Evaluation of Risk Factors for Infection among Patients Receiving Ibrutinib." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S572—S573. http://dx.doi.org/10.1093/ofid/ofaa439.1273.
Full textAbstract:
Abstract Background Ibrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK) approved for various B-cell malignancies and cGVHD. Rates of serious infection—defined as requiring hospitalization or parenteral antimicrobials— and invasive fungal infection (IFI) in patients on ibrutinib are as high as 11.4% and 4.2% respectively (Varughese T, et al. Clin Infect Dis 2018;67(5):687-92), which may be related to off-target inhibition of interleukin-2-inducible T-cell kinase or macrophage function. Methods We retrospectively reviewed infection complications in patients receiving ibrutinib at our institution between 06/01/2014 and 08/31/2019, including patients who received single-agent or combination ibrutinib. In this study, serious infection was defined as above, or a diagnosis of pneumonia regardless of hospitalization or parenteral antimicrobial therapy. Logistic regression was used to identify risk factors. Results Baseline characteristics of 134 included patients are in Table 1. Infection and serious infection occurred in 96 (72%) and 48 (36%) patients, respectively. When pneumonia was not included as a criterion for serious infection, the serious infection rate was 22%. Prior allogeneic stem cell transplant (allo-HSCT) (OR 4.50; 95% CI 1.19 – 17.00) and corticosteroid use (OR 5.42; 95% CI 1.49 – 19.82) were significant risk factors for serious infection without pneumonia (Table 2). Of 37 patients (28%) who received primary HSV/VZV prophylaxis with acyclovir, there was one case of suspected herpes zoster infection (3%). IFI developed in 7 patients (5%): 5 with Pneumocystis jirovecii pneumonia (PJP), 1 with invasive aspergillosis, and 1 with a filamentous fungus, species unknown. Other identified organisms are detailed in Figure 1. Classical risk factors for IFI, including diabetes, allo-HSCT, and concurrent corticosteroid use, were not significant predictors in this group. Table 1. Baseline Characteristics Table 2. Risk Factor Analysis Figure 1. Identified Organisms in Serious Infection Conclusion Serious infections developed at a higher rate than previously reported in the literature, with IFI rates similar to those previously described. Prior allo-HSCT and steroid use were found to be risk factors for serious infection without pneumonia. Treating physicians should have a high index of suspicion for pneumonia, IFI, and PJP in this population. Disclosures All Authors: No reported disclosures
44
de Wit, K., M. Mercuri, C. Varner, S. Parpia, S. McLeod, N. Clayton, C. Kearon, and A. Worster. "PL03: Prevalence and clinical predictors of intracranial hemorrhage in seniors who have fallen." CJEM 21, S1 (May 2019): S5—S6. http://dx.doi.org/10.1017/cem.2019.42.
Full textAbstract:
Introduction: The Canadian population is aging and an increasing proportion of emergency department (ED) patients are seniors. ED visits among seniors are frequently instigated by a fall at home. Some of these patients develop intracranial hemorrhage (ICH) because of falling. There has been little research on the frequency of ICH in elderly patients who fall, and on which clinical factors are associated with ICH in these patients. The aim of this study was to identify the incidence of ICH, and the clinical features which are associated with ICH, in seniors who present to the ED having fallen. Methods: This was a prospective cohort study conducted in three EDs. Patients were included if they were age >65 years, and presented to the ED within 48 hours of a fall on level ground, off a bed/chair/toilet or down one step. Patients were excluded if they fell from a height, were knocked over by a vehicle or were assaulted. ED physicians recorded predefined clinical findings (yes/no) before any head imaging was done. Head imaging was done at the ED physician's discretion. All patients were followed for 6 weeks (both by telephone call and chart review at 6 weeks) for evidence of ICH. Associations between baseline clinical findings and the presence of ICH were assessed with multivariable logistic regression. Results: In total, 1753 patients were enrolled. The prevalence of ICH was 5.0% (88 patients), of whom 74 patients had ICH on the ED CT scan and 14 had ICH diagnosed during follow-up. 61% were female and the median age was 82 (interquartile range 75-88). History included hypertension in 76%, diabetes in 29%, dementia in 27%, stroke/TIA in 19%, major bleeding in 11% and chronic kidney disease in 11%. 35% were on antiplatelet therapy and 25% were on an anticoagulant. Only 4 clinical variables were independently associated with ICH: bruise/laceration on the head (odds ratio (OR): 4.3; 95% CI 2.7-7.0), new abnormalities on neurological examination (OR: 4.4; 2.4-8.1), chronic kidney disease (OR: 2.4; 1.3-4.6) and reduced GCS from baseline (OR: 1.9; 1.0-3.4). Neither anticoagulation (OR: 0.9; 0.5-1.6) nor antiplatelet use (OR: 1.1; 0.6-1.8) appeared to be associated with ICH. Conclusion: This prospective study found a prevalence of ICH of 5.0% in seniors after a fall, and that bruising on the head, abnormal neurological examination, abnormal GCS and chronic kidney disease were predictive of ICH.
45
Wang, Weige, Franzen Carrie, Hui Guo, Jimmy Lee, Yan Li, Madina Sukhanova, Dong Sheng, et al. "Inhibition of B-Cell Receptor Signaling Disrupts Cell Adhesion in Mantle Cell Lymphoma Via RAC2." Blood 132, Supplement 1 (November 29, 2018): 1369. http://dx.doi.org/10.1182/blood-2018-99-118598.
Full textAbstract:
Abstract Background: B-cell receptor (BCR) signaling pathway is recognized as a crucial pathway for the pathogenesis of neoplastic B-cells. Inhibition of the BCR signaling and the downstream pathway is highly effective in B-cell malignancy through Bruton tyrosine kinase inhibition by ibrutinib. In addition to cell proliferation inhibition, ibrutinib disrupts cell adhesion between tumor and its microenvironment through unknown molecular mechanisms, resulting in peripheral lymphocytosis with accompanying lymphadenopathy reduction in patients who receive ibrutinib. Methods and materials: In an effort to elucidate the link between BCR signaling and cell adhesion phenotype, we first characterized ibrutinib sensitive and resistant mantle cell lymphoma (MCL) cell lines. We measured cell proliferation and cell growth, and correlated ibrutinib sensitivity with cell adhesion disruption. We then used RNA-sequencing to identify differential pathways between sensitive or resistant cell lines in response to ibrutinib treatment. We validated RNA-Seq findings using cell lines, as well as animal models and human primary MCL tumor tissues and cells. Results: We found that intrinsic sensitivities of MCL cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion gene signatures were simultaneously down-regulated by ibrutinib in ibrutinib-sensitive but not ibrutinib-resistant cell lines. Among the differentially expressed genes in the BCR gene signature, we identified and validated that RAC2, a regulator of cell adhesion, was down-regulated at both RNA and protein levels by ibrutinib only in ibrutinib-sensitive cells. Physical association of RAC2 with BLNK, an early BCR pathway adaptor, was disrupted by ibrutinib uniquely in sensitive cells. RAC2 knockdown with siRNA impaired cell adhesion while RAC2 over-expression rescued ibrutinib-induced reduction in cell adhesion. In a xenograft mouse model, mice treated with ibrutinib demonstrated tumor growth retardation along with down-regulation in RAC2 protein expression. Using immunohistochemical staining, we demonstrated that RAC2 was expressed in ~65% primary MCL tumor tissues with majority of RAC2-positive tumors characterized as being the more aggressive subtypes. Finally, primary MCL cells treated with ibrutinib demonstrated reduced RAC2 that is accompanied by cell adhesion impairment. Conclusions: Our findings uncover a novel cross-talk between BCR signaling and cell adhesion. Ibrutinib inhibits cell adhesion via down-regulation of RAC2. Our study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and new drug development. Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; AstraZeneca: Consultancy, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding.
46
Smooha, Gil, Yehudit Birger, Liat Goldberg, Jasmine Jacob-Hirsch, Ninette Amariglio, Gideon Rechavi, Ditsa Levanon, et al. "MODELING and Targeting ERG-INDUCED Acute MYELOID LEUKEMIA (AML)." Blood 114, no. 22 (November 20, 2009): 475. http://dx.doi.org/10.1182/blood.v114.22.475.475.
Full textAbstract:
Abstract Abstract 475 ERG is an oncogene located on the long arm of human chromosome 21 that encodes an ETS transcription factor that has been reported to be involved in normal and aberrant megakaryopoiesis (Salek-Ardakani et al Cancer Res. 2009;69:4665; Stankiewicz et al Blood 2009;113:3337). High ERG expression has also been reported associated with poor prognosis of cytogenetically normal AML (Marcucci et al J Clin Oncol. 2007;25:3337). Thus, deciphering the molecular targets and oncogenic pathways activated by overexpressed ERG protein is likely to lead to more effective therapy for ERG-related myeloid leukemias. Towards these goals we have combined in-vitro and in-vivo approaches. We have created transgenic mice expressing the ERG3 hematopoietic isoform under the VAV promoter. All these mice die from invasive acute megakaryocytic or undifferentiated myeloid leukemia by the age of 5 months. The leukemias are transplantable, and primary growth factor dependent leukemic cell lines, suitable for pharmacological and molecular studies, have been established. To identify ERG target genes and proteins, we have analyzed gene expression in two “mirror-image” cellular systems – shRNA mediated knockdown of ERG in Meg01 megakaryocytic leukemia cells and overexpression of ERG in K562 erythroleukemia cells. Gene Set Enrichment Analysis (GSEA) demonstrated that the “ERG gene-associated expression signature” in these cell lines is enriched with genes that were also identified in primary human AML characterized by ERG overexpression. By chromatin immunoprecipitation, we then identified specific, direct ERG targets and confirmed their expression in samples from ERG transgenic leukemias and primary human “ERG-overexpressing” AMLs. Surprisingly, we observed that the lymphoid kinase Bruton agammaglobulinemia tyrosine kinase (BTK) is an ERG direct target that is upregulated in both ERG overexpressing mouse and human leukemias. Preliminary experiments have demonstrated activity of a BTK inhibitor on ERG transgenic and ERG overexpressing human AML cells. ERG overexpression also induced marked activation of RAS signaling as supported by elevated levels of RAS-GTP and its downstream targets and significant growth inhibitory activity caused by a novel RAS inhibitor, farnesylthiosalicylic acid (Salirasib), that disrupts the spatiotemporal localization of active Ras (Rotblat et al Methods Enzymol. 2008;439:467) was observed. Dramatic growth inhibitory activity has also been induced by two novel compounds that induce megakaryocytic polyploidization, suggesting a potential role for “differentiation” therapy of ERG-related leukemias. Thus we have created a mouse model for ERG-related AML and characterized several genes and biochemical pathways that are susceptible to pharmacological inhibition. Our studies are not only likely to decipher the mechanisms by which ERG overexpression contributes to leukemogenesis, but also provide a platform for preclinical studies of novel therapeutics of these poor prognosis leukemias. Disclosures: No relevant conflicts of interest to declare.
47
Sarpatwari, Ameet, Shirley Watson, Howard Anderson, Drew Provan, and Adrian Newland. "Health-Related Lifestyle among Adult & Pediatric Patients with Idiopathic Thrombocytopenic Purpura in the United Kingdom." Blood 112, no. 11 (November 16, 2008): 3435. http://dx.doi.org/10.1182/blood.v112.11.3435.3435.
Full textAbstract:
Abstract Idiopathic thrombocytopenic purpura (ITP) is an autoimmune condition characterized by autoantibody-mediated platelet destruction and suboptimal megakaryocytic production. Primarily acute (< 6 months) in duration among children, ITP manifests predominantly chronically among adults, increasing susceptibility to bleeding events. Despite recent growth, published literature on health-related quality of life in ITP remains limited. The objective of our investigation was to identify lifestyle concerns associated with ITP among adult and pediatric patients in the United Kingdom. In collaboration with ITP specialists, a 43 question, closed-field lifestyle survey was developed, addressing social engagement, work and school performance, sports and activities, treatment, and travel. Patient members of the United Kingdom ITP Support Association (N = 1,767) were asked to complete and return mailed surveys. Pearson’s chi-square and Fisher’s exact tests were used to evaluate differences in dichotomized variables between groups. 790 (45%) completed surveys were returned. As illustrated in the table below, roughly one-quarter of adults (≥ 16 years) and one-fifth of children reported ‘always’, ‘sometimes’, or ‘often’ missing school or work owing to fatigue and having encountered difficulty obtaining insurance. Nearly one-third of adults further revealed having an elective surgery delayed owing to a low platelet count. Disparities were noted across gender with regard to bruise concealment (adults: p < 0.01; children: p = 0.03) and suspicions of subjection to violence (adults: p < 0.01; children: p = 0.49). In contrast with adults, pediatric patients reported being more likely to having requests for referral denied (p = 0.03). This study represents the largest quality of life investigation of ITP to date. Although the survey utilized remains to be validated, its findings nonetheless successfully highlight avenues for future investigation. Subgroups: ‘Yes’ % Adults Children Question Total ‘Yes’ % N = 790 Male N = 199 Female N = 497 Male N = 51 Female N = 43 [1] Total number of responses recorded for the given question. Have you ever been unable to go to work or school because of tiredness and fatigue? 29% 710[1] 26% 186 31% 435 20% 49 30% 40 Have you had difficulty obtaining or been refused travel and life insurance? 29% 611 30% 540 18% 71 Have you ever had surgery (other than splenectomy for ITP) postponed or delayed because of a low platelet count? 30% 620 34% 158 30% 391 13% 39 19% 32 Do you try to hide your bruises? 29% 756 10% 190 37% 475 20% 50 42% 41 Are people ever suspicious that the bruises are a result of physical violence? 17% 750 5% 193 19% 468 31% 49 38% 40 Have you ever been refused a referral to an ITP specialist or hospital of 5% 574 3% 144 4% 358 10% 41 10% 31
48
Ma, Qiufei, Simarjeet Kaur, Angela Zhao, Jie Zhang, Roberto Javier Ramos, Dinesh Kumar, Lokho John, Lida Bubuteishvili Pacaud, and Alessandra Forcina. "Systematic Literature Review of the Clinical Efficacy, Safety, and Patient-Reported Outcomes of Treatments in Patients with Relapsed or Refractory Follicular Lymphoma after Two Prior Therapies." Blood 136, Supplement 1 (November 5, 2020): 40. http://dx.doi.org/10.1182/blood-2020-137769.
Full textAbstract:
Introduction For patients (pts) with relapsed or refractory follicular lymphoma (r/r FL) beyond front-line therapy, there is no well-defined standard of care (SOC) treatment, especially in the third-line or later (3L+) setting. Treatment decisions for symptomatic patients depend on comorbidities, extent of disease, lines of prior therapy and duration of response to initial anti-CD20 containing treatment. Treatment options for 3L+ may include similar options to the ones in earlier lines, with a preference for non-cross-resistant schemes. Recently, a plethora of new compounds are being studied in clinical trials. A systematic literature review (SLR) was conducted to identify relevant evidence on clinical outcomes in pts with r/r FL, including conventional treatments and emerging compounds, within the 3L+ setting. Methods We performed a SLR on March 17, 2020. Clinical trials and observational studies were searched through Embase, PubMed, and Cochrane Central Register of Controlled Clinical Trials from 1998 to 2020, followed by relevant conference proceedings and regulatory documents. Evidence assessing any intervention as 3L+ FL and published in English language was included. If a study included broader indolent non-Hodgkin's lymphoma (iNHL) pts, only FL data was reported; if a study included pts with fewer than 3L+, 3L+ data was included, with mixed line results excluded. Conventional treatments, defined as approved or clinical guideline recommended treatments, included anti-CD20 monoclonal antibody (mAb)-containing regimen, mAb alone, chemotherapy alone, phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib), lenalidomide + rituximab (R2), radio-immunotherapy (RIT) with yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, autologous and allogeneic stem cell transplantation (auto- and allo-SCT). Emerging compounds included new treatments that are not approved but were tested in the context of clinical trials (bruton tyrosine kinase inhibitors, bortezomib, polatuzumab vedotin, daratumumab, inotuzumab, bi-specific T-cell engaging CD19 mAb, anti-CD19 chimeric antigen receptor T-cell [CAR-T] therapy). Results Of the 3747 publications identified, 74 studies assessing 26 treatment regimens, including conventional ones like rituximab (R)-containing immunochemotherapy to emerging compounds such as CAR-T therapies, were selected. Across the conventional regimens, 7 studies reported clinical trial data with relatively large 3L+ FL populations (Table 1). With R monotherapy, PI3K inhibitors and tazemetostat, the reported complete response (CR) rates and overall response rates (ORR) ranged from 1-20% and 34-77%, while median duration of response (mDOR) ranged between 7.9-16.3 months. Three clinical trials with PI3K inhibitors reported proportions of pts achieving a response of at least 6 months in duration ranging from 18-30%; median progression-free survival (mPFS) ranging from 8.3-11.2 months. For tazemetostat, mPFS was 11.0 months in EZH2 mutant vs 5.7 months in wild-type FL. With allo-SCT, 2-yr PFS rate was 88% and 57% for pts with CR and PR, respectively. Overall survival (OS) data varied: median overall survival (mOS) was 28-38 months for PI3K inhibitors while mOS was up to 85 months after allo-SCT, despite high non-relapse mortality (NRM) rates with most common causes of death being graft-versus-host disease (GvHD) and infections. Safety profiles were also different across treatments, with most common side effects being hepatotoxicity, diarrhea and infections (PI3K inhibitors) to GvHD (allo-SCT). Three trials presented patient-reported outcomes (PRO) data, all using the Functional Assessment of Cancer Therapy (FACT) questionnaire. Two studies with PI3K inhibitors demonstrated favorable or clinically significant improvement on pts quality of life (QoL), but 1 allo-SCT trial did not show a significant difference between baseline and 2 years post-transplant scores. Conclusion To our knowledge, this is the first SLR focusing on 3L+ treatments of FL. Heterogeneity in study design, patient population, safety profile and reported outcomes make it challenging to identify an optimal treatment regimen for FL in the 3L+ setting. More PRO data are needed considering the important role pt QoL plays in treatment selection. Disclosures Ma: Novartis:Current Employment.Kaur:Novartis:Current Employment.Zhao:Novartis:Current Employment.Zhang:Novartis:Current Employment.Ramos:Novartis:Current Employment.Kumar:Novartis:Current Employment.John:Novartis:Current Employment.Bubuteishvili Pacaud:Novartis:Current Employment.Forcina:Novartis:Current Employment.
49
Kuroda, Junya, Taku Tsukamoto, Shingo Nakahata, Kazuhiro Morishita, Ryuichi Sato, Akinori Kanai, Toshiya Inaba, Masakazu Nakano, Kei Tashiro, and Masafumi Taniwaki. "Genome-Wide Analysis of BRD4-Targets Reveals the Therapeutic Relevance of Simultaneous Targeting of BCR Pathway and IKZF-MYC Axis in Mantle Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 4100. http://dx.doi.org/10.1182/blood-2018-99-109982.
Full textAbstract:
Abstract Mantle cell lymphoma (MCL) has been mostly incurable, and there is an urgent need to identify targetable molecules for development of a more effective treatment strategy. Bromodomain and extraterminal domain (BET) proteins associate with acetylated histones and facilitate transcription of target genes, and bromodomain-containing 4 (BRD4), a member of BET proteins, recruits the P-TEFb complex to genomic lesions in chromatin and thereby activates RNA Pol II at specific promoter sites of target genes. In addition, super-enhancers have been recognized as regulatory regions with a high level of acetylated histones, mediator complexes and BRD4, and super-enhancers in cancer cells are enriched at oncogenes. Recent studies have shown that BRD4 promotes expression of pivotal molecules in disease development, maintenance and progression in various cancers, including lymphoma. Given, we in this study examined the effect of BRD4 inhibition on human MCL-derived cell lines, Jeko-1, JVM-2, MINO and Z138, and performed broad screening of BRD4-regulated molecules using genome-wide approaches to identify therapeutic targets for MCL. As the results, treatment with a BRD4 inhibitor I-BET151 for 72 h showed a dose-dependent inhibitory effect on cell proliferation in all four cell lines, with half maximal inhibitory concentrations (IC50s) of 15.6 nM, 3.6 nM, 2.6 nM and 3.0 nM in Jeko-1 cells, JVM2 cells, MINO cells and Z138 cells, respectively, which was accompanied by G1/S cell cycle arrest and the induction of apoptosis. Next, we performed comprehensive gene expression profile (GEP) analysis for JVM2 and Z138 cells with or without I-BET151 treatment, and BRD4 chromatin immunoprecipitation sequencing (ChIP-Seq) in JVM2 cells treated with 10 nM I-BET151 or DMSO. Accordingly, GEP analyses revealed that more than 600 genes were commonly upregulated by more than 1.5-fold and downregulated by less than 0.67-fold, respectively, in JVM2 and Z138 cells treated by I-BET151, while ChIP-Seq showed that 7988 BRD4-binding regions were dysregulated by I-BET151, with most of these sites in enhancer regions, and 547 BRD4-binding regions were characterized as super-enhancers. Integrated analysis using the Reactome Pathway Database and the results of GEP and ChIP-Seq showed that a series of genes involved in the B cell receptor (BCR) signaling pathway and IKZF-MYC axis are regulated by BRD4 in MCL cells. To confirm whether each BRD4 target contributes to survival and proliferation of MCL cells, we focused on several candidate targets: the BCR pathway, IKZF and MYB. However, ibrutinib, a Bruton kinase inhibitor, suppressed cell growth in only two of the four cell lines (MINO and JVM2) in a dose-dependent manner, while lenalidomide, an inhibitor of the IKZF family, did not affect cell survival, despite its potency in decreasing IKZF1 and IKZF3 proteins. MYB silencing using shMYB did not decrease cell proliferation in any of the four MCL cell lines. In conclusion, our study disclosed that BRD4 regulates transcription of multiple genes by binding to enhancer region, partly involving super-enhancers and multiple known pathways, such as BCR signaling and the IKZF-MYC axis, which play essential roles in survival of MCL cells. While the efficacy of single targeting of BCR-signaling, IKZF, or MYB was limited, I-BET151 concomitantly inactivated the BCR pathway and IKZF and had a high growth inhibitory efficacy in MCL cells. These results suggest that simultaneous targeting of multiple molecules involved in the BCR pathway and IKZF-MYC axis may overcome resistance to ibrutinib and/or lenalidomide in MCL, and that BRD4 inhibitors are promising candidates for MCL treatment. Disclosures Kuroda: Chugai Pharma: Honoraria, Research Funding. Taniwaki:Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.,: Research Funding; Astellas Pharma Inc,: Research Funding.
50
Calleja, Anne, Sandra De Barros, Camille Vinson, Caroline Protin, Lucie Oberic, Fanny Gallais, Melanie White-koning, et al. "Interest of Dosing of Ibrutinib in B-Cell Lymphoid Malignancies: Data from a Real-Life, Phase 4 Study." Blood 132, Supplement 1 (November 29, 2018): 3960. http://dx.doi.org/10.1182/blood-2018-99-116532.
Full textAbstract:
Abstract Introduction: Therapeutic drug monitoring (TDM) entails the measurement of drug concentrations and the individualization of drug dosages or schedules to maximize therapeutic effects and minimize toxicity. Ibrutinib (IBR), the first-in-class inhibitor of BTK (Bruton tyrosine kinase) is approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL), mantle cell lymphoma (MCL) and Waldenström's disease (WM), at the dose of 420-560mg/d. Drug-drug interactions (DDI), older age, liver diseases have been reported to impact PK parameters of ibrutinib, but dosing is not yet part of clinical practice, despite TDM of imatinib and other kinase inhibitors is routinely used in chronic myeloid leukemia. In this study, we sought to determine whether TDM of ibrutinib should be proposed for patients, in a preliminary cohort of 73 patients included in the PK-e3i trial (NCT02824159). Methods: Serial plasma PK samples were collected at steady-state after one month of therapy in 73 patients: before intake (residual concentration), and then at time 0.5-1-2-4-6h. Key PK parameters for ibrutinib and its metabolite DHD-ibrutinib were calculated: Cmax, Cmin, tmax,AUC24h. Analysis of DDI was made by an oncology pharmacist in 49/73 patients. Treatment-related adverse events were monitored by phonecalls given by an oncology nurse (AMA procedure) and during consultations with hematologist (at least twice a month the first 6 months, then monthly until 12 months, then every 3 months), and severity graded according CTCAE version 4 scale. Efficacy of therapy in CLL patients was assessed with an "effect marker" to demonstrate biological efficacy, the redistribution hyperlymphocytosis seen in 70% of patients the first month of therapy. Results: we reported very similar PK results for ibrutinib as compared to pivotal phase 1 trials in CLL and other B-cell lymphoid malignancies (Advani RH, J Clin Oncol 2013, Byrd JC, New Engl J Med 2013). Mean peak plasma concentrations were observed 1-2h after dosing, Cmax and AUC results showing an important inter-patient heterogeneity. Median Cmax was 150ng/ml (8.2-596ng/ml), and median AUC24h was 412.4 ng h/mL ((32.2-2906 ng h/mL). According to published phase I trials, complete or near complete BTK occupancy was observed in patients with AUCs exceeding 160 ng h/mL, suggesting ibrutinib dose might have been supramaximal in 67 of our patients. Adverse events the first 3 months were seen in 96% (grade 1), 63% (grade 2), 25% (grade 3) and 6.5% (grade 4), respectively. We plotted AUC results for the total cohort of 73 patients (Figure 1), and for 49 patients with adverse events monitoring available at 3 months (9/49 needed drug dose reduction due to toxicity) (Figure 2), both emphasizing the absence of correlations between AUC levels and toxicities. We next splited up toxicities into 10 sub-groups (bleeding, cardiac, liver, muscle, joint, skin, infection, gastro-intestinal, hematologic, neurologic disorders). Again, we could not identify a specific organ toxicity associated with a significant increase of Cmax or AUC24h, nor we could identify a specific DDI signature explaining side effects in our patents (data not shown: 13/49 had CYP3A4 inhibitors, 25/49 had pgp inhibitors). In 45 CLL patients with PK parameters and lymphocyte counts available after one month of therapy, we made the intriguing observation that lower Cmax correlated with the lack of observable, transient hyperlymphocytosis (a class-effect of ibrutinib, correlating with PFS in the Resonate trial) (Figure 3). Altogether, our data did not find any positive correlation between high ibrutinib exposure and efficacy or safety profile. Conclusions: our preliminary results suggested that higher Cmax and AUC24h did not correlate neither to efficacy nor to classical toxicities reported with ibrutinib intake. On one hand, we think that dosing intra-cellular concentrations could be more reliable than in plasma. On the other hand, we could consider TDM of ibrutinib in the context of a clinical trial reducing the doses of drug over time, to limit clinical and financial toxicity of this highly efficient drug. Disclosures No relevant conflicts of interest to declare.