The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ...ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.
Summary
In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual ...disease (MRD) detected by real time quantitative polymerase chain reaction (RQ‐PCR) and 3‐colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time‐points during treatment (93·38%), and a combined use of both approaches allowed a multi time‐point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0·01% were identified by RQ‐PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ‐PCR and FC approach, the evaluation of 367 follow‐up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0·04), >0·01% at the end of induction (P = 0·02), >0·01% at the end of consolidation (P = 0·01), >0·01% prior to the first delayed intensification (P = 0·01), and >0·1% prior to the second delayed intensification and continued maintenance (P = 0·001) were all associated with relapse and, based on early time‐points (end of induction and consolidation) a significant log‐rank trend (P = 0·0091) was noted between survival curves for patients stratified into high, intermediate and low‐risk MRD groups.
This article introduces a symposium on religion and the formation of modern urban space in Asia and Africa. Both the spread of new religious movements and the articulations between religion, ...globalization and neoliberalism have prompted new analyses of the shifting geographic and social boundaries between ‘religious’ and ‘secular’ institutions, practices and discourses, and about the meaning of ‘religion’ itself. We reinscribe work on urban religion within a discussion of ‘modernity’ by dealing with the socio‐spatial mediation of religion and its role in redefining public spaces, practices, norms and discourses in contemporary cities. Individual articles map the spaces engendered by religious imaginaries and the forms of mobility and networks that religion relies on and constitutes, and they identify and analyze the roles played by mass media in religious practice and institution building, as well as the embodied nature of urban religious experience. They demonstrate how urban studies can be ‘pluralized’ and ‘vernacularized’ through analyses of how the urban realm is constituted in part through religious practice and meaning. Our attention to the articulation of religion with cities in Asia and Africa will also help to foster a new theoretical vocabulary within religious studies that is attentive to the historical, cultural and spatial contingencies of religion as a category of analysis.
Résumé
Cet article présente un symposium sur la religion et la formation de l’espace urbain moderne en Asie et en Afrique. La propagation de mouvements religieux nouveaux, ainsi que les articulations entre religion, mondialisation et néolibéralisme, ont suscité des analyses originales sur le décalage des frontières géographiques et sociales entre les institutions, pratiques et discours “religieux” et “laïcs”, et sur la signification de la religion elle‐même. Nous réinscrivons les travaux sur la religion urbaine dans une discussion sur la “modernité” en abordant la médiation socio‐spatiale de la religion et son rôle dans la redéfinition des pratiques, normes, discours et espaces publics dans les villes contemporaines. Les différents articles recensent les espaces générés par les imaginaires religieux, ainsi que les formes de mobilité et de réseaux que la religion élabore et sur lesquelles elle s’appuie ; de plus, ils identifient et analysent les rôles des médias dans la pratique religieuse et la construction de l’institution, et s’intéressent à la matérialité de l’expérience religieuse urbaine. Ils montrent comment les études urbaines peuvent être “pluralisées” et “vernacularisées” par le biais d’analyses sur la façon dont l’univers urbain se constitue en partie par la pratique et la signification de la religion. De plus, notre intérêt pour l’articulation de la religion avec les villes d’Asie et d’Afrique contribue à alimenter un nouveau lexique théorique pour les études religieuses, qui veille aux contingences historiques, culturelles et spatiales de la religion en tant que catégorie analysée.
SAR studies are described, which led to the discovery of novel SERMs for the treatment of uterine fibroids.
Structure–activity relationship studies are described, which led to the discovery of novel ...selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.
FcγRIIA, a low affinity receptor for IgG, is a polymorphic molecule: FcγRIIA‐HH131, FcγRIIA‐HR131 and FcγRIIA‐RR131. This polymorphism influences the efficiency of the receptor to bind with IgG2. ...Recent reports on altered distribution amongst individuals with heparin‐induced thrombocytopenia (HIT) prompted us to examine the FcγRIIA polymorphism in a cohort of patients with refractory idiopathic (immune) thrombocytopenic purpura (ITP), in whom severe disease had required them to undergo splenectomy. 29 post splenectomy ITP individuals and 61 normal controls were investigated. Polymerase chain reaction (PCR) and a Southern blotting technique were used to determine the FcγRII polymorphism. Although the distribution of the allotypes of FcγRIIA in the control population was similar to that found in other European studies of Caucasian populations (15 (25%) HH131; 35 (57%) HR131; 11(18%) RR131), the patient group was skewed towards the RR131 allotype which has least efficiency for IgG2 binding (3 (10%) HH131; 12 (42%) HR131; 14 (48%) RR131; P < 0.005). These findings suggest that FcγRIIA polymorphisms may be implicated in the pathophysiology of ITP or may be responsible for modulating the immune response in this heterogenous autoimmune disease.
Symptomatic anterior myocardial ischemia as a result of stenosis at the origin of the left internal mammary artery developed in a patient who underwent prior coronary artery bypass grafting using the ...left internal mammary artery as a conduit. Successful revascularization of the left anterior descending coronary artery was achieved using a reversed saphenous vein bypass graft from the left common carotid artery to the proximal internal mammary artery. This approach provided myocardial revascularization and avoided reoperative median sternotomy.
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