bluuebunny/crossref_metadata_2025 huggingface dataset:
Ludic History in the Book of Judith: The Reinvention of Israelite Identity?
Authors: Esler Philip
Published: October 2002

The book of Judith bristles with issues of power, gender and ethnic identity. In this article the text is analysed using recent anthropolgical perspectives relating to the 'production of history' and an 'ethnography of the past'. It is argued that the text presents a ludic, even carnivalesque reworking of key themes in Israelite history. Judith equals or surpasses the achievements of great heroes in her people's past, such as David or Judas Maccabaeus, in a manner unknown to Graeco-Roman or Israelite traditions. All this is achieved through the agency of a decidedly liminal character in the form of a beautiful and wealthy Israelite widow, the full impact of whose achievements can only be assessed in the context of the honour-obsessed Mediterranean culture within which she functions. Finally, it is suggested that the text succeeds in re-imagining and reinventing Israelite identity. By regendering central themes of Israelite history, the text re-engenders Israel.
HERONDAS 8.66-79: GENERIC SELF-CONSCIOUSNESS AND ARTISTIC CLAIMS IN HERONDAS' MIMIAMBS
Authors: Fountoulakis Andreas
Published: October 2002

In Herondas' mimiamb 8, a poem particularly concerned with questions of generic identity and reception, the poet defends his work and puts forward his literary program by means of a dream dominated by images related to Dionysiac myth and cult. The interpretation of the dream at ll. 66-79 is seen in terms of the generic affinities between Herondas' mimiambs, the iambographic tradition of Hipponax and the mime. In this paper the Dionysiac character of those images is not considered as an indication of a hypothetically dramatic nature of Herondas' work. It is argued, by contrast, that the poem's Dionysiac imagery and its subsequent interpretation are linked with the associations of Herondas' work with the mime and, more specifically, with the non-literary mime. Mimiamb 8 is considered as part of a long process through which the latter was eventually regarded as a dramatic genre. Herondas seems to be conscious of the disreputable character of that part of his sources, but attempts by means of a masterful use of images pertaining to Dionysiac myth and ritual to persuade his critics of the dramatic nature of the mimic origins of his work so as to invest his poetry with the authority and prestige of dramatic poetry.
KING OR PRIVATE CITIZEN: FIFTH-CENTURY SICILIAN TYRANTS AT OLYMPIA AND DELPHI
Authors: Harrell Sarah
Published: October 2002

We possess an array of contemporary evidence relating to the fifth-century Deinomenid tyrants of Sicily. Epinician poetry and physical monuments that the tyrants themselves commissioned still survive. The poems and dedications celebrate the tyrants at roughly the same time, sometimes in response to the same events. These documents do not demonstrate the constitutional or legal position of the historical tyrants. Instead they allow us a view into how the tyrants represented themselves as political actors in different contexts and before different audiences. Whether occasioned by an athletic or martial victory, both poetry and monuments depicted the tyrants as panhellenic figures who benefited their city and their subjects. Yet when placed side by side, the poetry and monuments reveal a striking disconnect between the representation of political power within their respective genres. The poets tackled the problem of tyranny head on. Before a local audience, epinician poetry portrayed the tyrant Hieron as a benevolent epic king. The monuments erected at Olympia and Delphi took a less direct approach. While celebrating the Deinomenids as private benefactors of the panhellenic sanctuaries, the dedicatory inscriptions avoided explicit articulation of the tyrants' political status at home.
THE USE OF THE DEFINITE ARTICLE IN THE DEVELOPMENT OF SOME BIBLICAL TOPONYMS
Authors: Lee S. Noah
Published: October 2002

Biblical Hebrew like other languages exhibits diachronic linguistic changes. One such linguistic change observable in the Hebrew Bible is the use of the definite article in the development of some biblical toponyms. What is behind the different forms of the same place-name, such as 'the Mount Gilboa' ( ) in 1 Sam. xxxi 1 vs. 'Mount Gilboa' ( ) in 1 Ch. x 1? It is observed that the use or absence of the article is by no means an accident but the result of a semantic change over a long period of use by the linguistic community. Furthermore, the use of the article in the development of toponyms shows the relative dates of writing of biblical books. The outcome of the study indicates the archaic character of the books of the Pentateuch and Joshua, and relative late dates of writing of Chronicles, Ezra and Nehemiah.
NIMROD THE MIGHTY, KING OF KISH, KING OF SUMER AND AKKAD
Authors: Levin Yigal
Published: October 2002

The intent of this paper is to examine the story of Nimrod in Genesis x 8-12, offering fresh insight on both the historical background and the literary development of the passage. The article deals first with the passage's literal meaning, syntax and the extant text. The geographic context of the passage is shown to be distinctly Mesopotamian-Nimrod being the "builder" of Babylon, Erech, Accad and other southern Mesopotamian cities and then moving north to Assyria. After surveying previous attempts to identify an "historical" Nimrod, the author then suggests that the biblical figure is modeled after the combined traditions about Sargon of Akkad and his grandson, Naram-Sin. Nimrod is the son of "Cush"; Sargon began his royal career at Kish right after the flood. The Sargon-Naram-Sin traditions reached the Levant during the second millennium BCE, being combined by time and distance into a composite personality. The tradition reached its final form during the reign of Sargon II of Assyria, who added such themes as hunting to the story. The later editors of the Book of Genesis dropped much of the story and the Nimrod tradition was thus lost to later generations, save five remaining verses in the tenth chapter of Genesis.
THE LIMITATIONS OF RELIGIOUS ENVIRONMENTALISM FOR INDIA
Authors: Tomalin Emma
Published: October 2002

Many environmentalists draw upon religious teachings to argue that humanity ought to transform its relationship with the natural world. They maintain that religious systems teach that the earth is sacred and has an intrinsic value beyond its use value to humanity. However, whilst many cultures have religious practices or teachings associated with the natural world, such traditions of nature religion ought to be distinguished from religious environmentalism. This paper suggests that religious environmentalism is limited because it is a product of Western ideas about nature, in particular a 'romantic' vision of nature as a realm of purity and aesthetic value. Although in India, for example, people worship certain trees, this is not evidence of an inherent environmental awareness, if only because such practices are very ancient and pre-date concerns about a global environmental crisis. Moreover, many people in developing countries, such as India, are directly dependent upon the natural world and cannot afford radically to alter their behaviour towards nature to accommodate religious environmentalist goals.
LIBERAL ECONOMICS AND THE INSTITUTIONALIZATION OF SIN: CHRISTIAN AND STOIC VESTIGES IN ECONOMIC RATIONALITY
Authors: Glenna Leland
Published: October 2002

The recognition that ecological problems often extend beyond nation-state boundaries has prompted environmentalists, politicians, and academics to call for and generate problem-solving discourses meant to be global in perspective. Free-market rhetoric has emerged as one of the more prominent of the global discourses, even though the free market's commodification of human beings and nature causes many environmental problems. To discredit this economic rationality, many scholars have compared it to religion. These comparisons are intriguing, but they have lacked the critical analysis necessary to appear as anything more than name-calling. This paper clarifies the definition of religion and uses it to examine the origins of economic rationality's fundamental presupposition—that greedy self-interested competition generates more social benefits than altruistic cooperation—within eighteenth-century Natural Law vs. Ecclesiastical Law debates. Despite economic rationality's adoption of sophisticated empirical methods and mathematical rigor over the past two centuries, it is a religion because it retains vestiges of the Protestant Christian and Stoic beliefs of how social life is governed by supernatural intervention when it uncritically promotes policies based on that presupposition. Recognizing economic rationality is a religion may benefit those who are striving to develop systems of governance based on democratic principles by leading to a greater understanding of economic rationality's normative attraction.
RACHEL CARSON'S ENVIRONMENTAL ETHICS
Authors: Cafaro Philip
Published: October 2002

Rachel Carson is well known as a founder of the modern environmental movement. This article argues that her life and writings have much to offer contemporary environmental philosophy. I begin by discussing the environmental ethics articulated in Silent Spring. I next examine Carson's earlier natural history writings and the non-anthropocentrism they express. I conclude with some suggestions for how Carson points the way forward for environmental ethics.
"WHAT IS APOLLOS? WHAT IS PAUL?" IN SEARCH FOR THE COHERENCE OF FIRST CORINTHIANS 1:10-4:21
Authors: Smit Joop
Published: October 2002

The coherence of 1 Cor. 1:10-4:21 is studied in three steps. With regard to the textual syntax it is shown that this passage consists of an introduction (1:10-17), followed by four separate sections elaborating first the theme of wisdom (1:18-2:5; 2:6-3:4) and next the division among the Corinthians (3:5-4:5; 4:6-21). At the semantic level it is argued that adherents of Apollos are Paul's main target and that in 1:18-19 he alludes to them. Further it is clarified that in rejecting σoϕiα λoγoυ he does not attack rhetoric as such, but human reasoning which they greatly admire. Finally a pragmatic analysis demonstrates that, following classical status theory, Paul defends himself in four steps against the depreciatory opinion adherents of Apollos harbor against him.
Acoustical mother-offspring recognition in pigs (sus scrofa domestica)
Authors: Illmann Gudrun , Schrader Lars , Špinka Marek , Šustr Pavel
Published: October 2002

Parental recognition of offspring is important in highly social animals. Both wild and free-ranging domestic sows live in groups during lactation, except for a few days of isolation directly after parturition. It is therefore important that a sow is able to discriminate her own piglets from alien piglets both at close contact and from a distance. We investigated whether piglets' vocalizations at 10 days of age may serve this function. Vocalizations of own and alien piglets were recorded on day 9 post partum whilst the piglets were isolated from the sow for 5 min (isolation calls, i-calls) and when piglets were returned to their sows afterwards (contact calls, c-calls). We first examined whether the two types of piglet vocalizations include cues which make it possible to discriminate between individual litters. A total of 2155 i-calls and 475 c-calls were sampled. From digitized calls, a total of 50 acoustic parameters were calculated and then subjected to a discriminant function analysis (forward stepwise method). Both i-calls and c-calls could be classified significantly better to the correct litters than would be expected by chance. In a playback experiment, whether sows isolated from their piglets respond more strongly to i-calls and c-calls of their own piglets than to alien calls was tested. For both the i-calls (N = 12 sows) and c-calls (N = 8 sows) sows responded with more vocalizations to the playback of own piglets' voices than to the playback of alien piglets' voices. The study shows that piglet calls contain acoustic cues that are litter typical and that sows are able to recognize their offspring based on these cues.
Aggression to dummy cuckoos by potential European cuckoo hosts
Authors: Røskaft Eivin , Moksnes Arne , Stokke Bård , Bicík Vítezslav , Moskát Csaba
Published: October 2002

Aggression directed by 53 potential host species towards a dummy of the parasitic common cuckoo, Cuculus canorus, was tested in relation to their breeding habitat, their suitability as a host and whether they were breeding in sympatry or not with the cuckoo. Host habitats were divided into three categories: (1) always breeding near trees, (2) some populations breeding near trees, others in open areas, and (3) always breeding in open areas. Each species was also placed in one of five categories according to their suitability as a cuckoo host. Strong support was found for predictions derived from the 'spatial habitat structure hypothesis', which argues that common cuckoos only breed in areas where they have access to vantage points in trees. Thus, species which have some populations breeding near trees and others breeding further from trees have a different cuckoo-host population dynamics than species that always breed near trees, or always breed in open areas. Aggression levels were highest among species regarded as being always suitable as hosts, and species which always breed near trees. However, populations breeding in sympatry with the cuckoo were more aggressive than allopatric populations, indicating the plasticity of aggressive behaviour. Adaptive behaviour in cuckoo hosts can be predicted from the 'spatial habitat structure hypothesis'.
Costs associated with recognition and rejection of parasitic eggs in two European passerines
Authors: Stokke Bård , Honza  , Moksnes  , Røskaft  , Rudolfsen
Published: October 2002

Many avian brood parasite hosts accept parasitic eggs even though successful parasitism frequently is detrimental to their own reproduction. Such behaviour seems suboptimal, but has been explained by the existence of opposing selective pressures operating against the evolution of appropriate host defence. Costs associated with rejection and recognition of eggs are central topics in this respect. Here, we report the occurrence of such costs in two European passerines (chaffinches and blackcaps) that are good rejecters of foreign eggs, even though the common cuckoo does not presently use them as hosts. Since high rejection rates are maintained in the absence of parasitism, we predicted that few recognition errors are made by these species. We tested this prediction by monitoring the occurrence of such errors in both experimentally parasitised and non-parasitised host clutches. We found support for the prediction, as our results show that recognition errors are at best rare events in these two species. We discuss the role of intraspecific brood parasitism as well as other explanations for the retention of a high rejection rate in these species. Various studies have reported mixed support for the occurrence of recognition errors among cuckoo hosts, and we consider other explanations for the existence of both acceptors and rejecters of foreign eggs in host populations.
MAKING ALL EXPERIENCE RELIGIOUS: THE HEGEMONY OF RITUAL AT QUMRAN
Authors: Kugler Rob
Published: October 2002

This study provides a preliminary inventory of the evidence for ritual density and change at Qumran. Then insights from ritual studies and the study of oral-literate cultures are used to formulate a hypothesis regarding the meaning of Qumran ritual intensity and relate it to the group's religious experience. We learn that ritual exercised measurable hegemony over the people at Qumran, making large portions of their experience "religious" in a certain sense, and that some of their ritual practices set them apart from other Jews. The study also indicates the basis for the group's ritual practices, their interpretation of Jewish scriptures.
Sociological definitions, language games, and the "essence" of religion
Authors: McKinnon Andrew
Published: October 2002

Sociologists of religion have long debated the definition of religion. In this article, I survey the debate and find a partially hidden consensus. This debate, in conjunction with recent criticisms of the concept "religion" in religious studies, and by drawing on Ludwig Wittgenstein's notion oflanguage games, provides helpful pointers for developing a non-essentialist conception of religion. I argue that "religion" (as a phenomenon and as a concept) is a historical and social construction, but that this does not require us to dispense with the concept altogether.
ORDINATION RITES AND PATRONAGE SYSTEMS IN THIRD-CENTURY AFRICA
Authors: Stewart-Sykes Alistair
Published: October 2002

The principal purpose of this paper is to describe the ordination rites of third century Africa. Beside describing these rites, we shall seek to understand their historical growth through observing the manner in which their social context both represents a wider social reality and constructs a new social world within the church. This social world may be described as "contra-cultural", in that it depends on the norms of the wider society for its existence, whilst inverting the values of that society. The social world of the African church has already been recognized as discrete and separate, and church order has already been understood within contra-cultural categories. This article explores one facet of this phenomenon within the society of the African church, namely the manner in which patronage both supplies a social norm and is inverted within the church, and explores the manner in which ritual may contribute to the construction of this society.
Soil evolution and development of the clay mineral assemblages of a Podzol and a Cambisol in ‘Meggerwald’, Switzerland
Authors: Egli M. , Zanelli R. , Kahr G. , Mirabella A. , Fitze P.
Published: October 2002

Two soils, a haplic Podzol and a dystric Cambisol, developed from post-glacial tills, were studied with respect to their soil chemistry and clay mineralogy. Although the state factors (age, geology, topography, climate) of soil formation were almost identical, two different types developed. The E horizon of the Podzol contained more smectite, characterized by a montmorillonite-beidellitemixed phase. The neoformation of smectite could be traced back to the weathering of mica and chlorite. The Podzol had less hydroxy-interlayered smectite (HIS) in the surface horizons than the Cambisol. A larger amount of chelating compounds in the E horizon of the Podzol either transformed HIS into smectites or inhibited the formation of HIS and favoured the formation of smectites. The physical structure of the soil material is believed to be the most important factor in the different modes of soil evolution. The greater abundance of coarse pores in the topsoil at the Podzol site probably led to a faster eluviation of base cations, a different vegetation at ground level, and, consequently, to a faster soil evolution with the formation of spodic horizons.
Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells
Authors: Scandella Elke , Men Ying , Gillessen Silke , Förster Reinhold , Groettrup Marcus
Published: October 2002

Dendritic cells (DCs) are potent antigen-presenting cells that are able to initiate and modulate immune responses and are hence exploited as cellular vaccines for immunotherapy. Their capacity to migrate from peripheral tissues to the T-cell areas of draining lymph nodes is crucial for the priming of T lymphocytes. In this study, we investigated how the maturation of human monocyte-derived DCs (MoDCs) by several different stimuli under serum-free conditions affected their T-cell stimulatory function, cytokine secretion, and migratory behavior. Surprisingly, we found that for all maturation stimuli tested, the addition of prostaglandin E2 (PGE2) was required for effective migration of MoDCs toward the lymph node–derived chemokines CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein–-3β) and CCL21 (secondary lymphoid tissue chemokine [SLC]/6Ckine). Costimulation with PGE2 enhanced the expression of the CCL19/CCL21 receptor CCR7 on the cell surface of MoDCs when they were matured with soluble CD40 ligand or proinflammatory cytokines, but did not affect CCR7 expression of polyI:C–stimulated MoDCs. The effects of PGE2 on MoDCs were mediated through increased cyclic adenosine monophosphate by 2 of the known PGE2 receptors, EP2 and EP4, which are expressed and down-regulated after PGE2 binding in these cells. In conclusion, our results suggest that signals provided by the proinflammatory mediator PGE2 are crucial for MoDCs to acquire potent T-helper cell stimulatory capacity and substantial chemotactic responsiveness to lymph node–derived chemokines. This is a new and important parameter for the preparation of MoDCs as cellular vaccines in tumor immunotherapy.
Regulation of iron absorption in Hfe mutant mice
Authors: Ajioka Richard S. , Levy Joanne E. , Andrews Nancy C. , Kushner James P.
Published: October 2002

Hereditary hemochromatosis is most commonly caused by homozygosity for a point mutation (C282Y) in the human hemochromatosis gene (HFE). The mechanism by which HFEregulates iron absorption is not known, but the C282Y mutation results in loss of cell surface expression of the human hemachromatosis protein (HFE) and hyperabsorption of iron by the duodenal enterocyte. Mice homozygous for a deletion in the mouse hemochromatosis gene (Hfe) or a mutation equivalent to that seen in human hereditary hemochromatosis (C282Y) were compared with wild-type animals for their ability to regulate iron absorption. Both mutant strains hyperabsorbed 59Fe administered by gavage. Feeding a diet supplemented with carbonyl iron resulted in a more than 5-fold reduction of 59Fe absorption in both wild-type and mutant mouse strains. Similarly, the iron loading associated with age inHfe mutant mice resulted in nearly a 4-fold reduction in iron absorption. When mice were stimulated to absorb iron either by depleting iron stores or by inducing erythropoiesis, wild type andHfe mutant strains increased absorption to similar levels, approximately 5-fold over control values. Our data indicate thatHfe mutant mice retain the ability to regulate iron absorption. Mouse hemachromatosis protein (Hfe) plays a minor role in down-regulation but does not influence the up-regulation of iron absorption.
Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy
Authors: Brown Brian D. , Lillicrap David
Published: October 2002

Recent studies in gene transfer suggest that the innate immune system plays a significant role in impeding gene therapy. In this review, we examine factors that might influence the recruitment and activation of the innate system in the context of gene therapy. We have adopted a novel model of immunology that contends that the immune system distinguishes not between self and nonself, but between what is dangerous and what is not dangerous. In taking this perspective, we provide an alternative and complementary insight into some of the failures and successes of current gene therapy protocols.
Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells
Authors: Witkowski Jacek M. , Zmuda-Trzebiatowska Emilia , Swiercz Jakub M. , Cichorek Miroslawa , Ciepluch Hanna , Lewandowski Krzysztof , Bryl Ewa , Hellmann Andrzej
Published: October 2002

Decreased susceptibility to apoptosis and impaired proliferative control are thought to be responsible for prolonged life span and accumulation of chronic lymphocytic leukemia (B-CLL) cells. The activity of calpains (calcium-dependent, neutral proteases, active in the cells responding to signals inducing a rise of cytoplasmic Ca++) is involved in the regulation of apoptosis of some cell types by interaction with caspase-3. This work verifies the hypothesis of the abnormal activity of calpains and its role in reduced apoptosis of the B-CLL cells. Casein zymography, reverse transcriptase–polymerase chain reaction, and Western blotting were used for identification and quantification of the activity and expression of calpains in B-CLL cells and purified normal B lymphocytes. The activity and expression of μ-calpain (requiring micromolar Ca++ for activation) are significantly higher in the leukemic than in nonmalignant cells. Contrarily, the activity and expression of m-calpain (requiring millimolar Ca++) as well as the expression of calpastatin (an endogenous inhibitor of calpains) are unchanged or reduced in the B-CLL lymphocytes. Correspondingly, the activity of caspase-3 is many times lower in the B-CLL cells than in normal B lymphocytes. Inhibition of overexpressed μ-calpain in living B-CLL cells in vitro results in doubling of the proportion of the cells undergoing spontaneous apoptosis. This observation suggests a possible role for calpains in longer survival of the B-CLL cells and may open new therapeutic possibilities.
Analysis of HIV-1–  and CMV-specific memory CD4 T-cell responses during primary and chronic infection
Authors: Harari Alexandre , Rizzardi G. Paolo , Ellefsen Kim , Ciuffreda Donatella , Champagne Patrick , Bart Pierre-Alexandre , Kaufmann Daniel , Telenti Amalio , Sahli Roland , Tambussi Giuseppe , Kaiser Laurent , Lazzarin Adriano , Perrin Luc , Pantaleo Giuseppe
Published: October 2002

CD4 T-cell–specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1– and CMV-specific interferon-γ–secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1–specific CD4 T-cell responses. A substantial proportion of CD4+CCR7− T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.
Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia
Authors: Bellosillo Beatriz , Villamor Neus , López-Guillermo Armando , Marcé Silvia , Bosch Francesc , Campo Elias , Montserrat Emili , Colomer Dolors
Published: October 2002

The role of Bax and Bak, 2 proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone, or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n = 33;r = 0.836; P < .001) or Bak (n = 10;r = 0.948; P < .001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (ΔΨm); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are caspase independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but do not seem to be essential in inducing Bax and Bak conformational changes, as they are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria and the conformational changes of Bax and Bak are among the early steps in the induction of cell death.
Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen–presenting cells
Authors: Mapara Markus Y. , Kim Yong-Mi , Wang Sheng-Ping , Bronson Roderick , Sachs David H. , Sykes Megan
Published: October 2002

In mice, donor leukocyte infusion (DLI) given to established mixed allogeneic chimeras can mediate powerful graft-versus-host (GVH) reactions confined to the lymphohematopoietic system without inducing graft-versus-host disease (GVHD). In a clinical trial attempting to capture this approach to achieve graft-versus-leukemia/lymphoma (GVL) effects without GVHD, we have observed surprisingly powerful antitumor effects of DLI in patients achieving mixed chimerism after nonmyeloablative bone marrow transplantation. This observation led us to hypothesize that host antigen–presenting cells in mixed chimeras might be required to optimally present recipient antigens to the donor lymphocytes, leading to maximal graft-versus-tumor effects. To test this hypothesis, we established mixed and fully allogeneic hematopoietic chimeras in B6 mice and evaluated the effect of DLI on EL4 T-cell lymphoma. DLI administration to mixed chimeras produced dramatically improved leukemia-free survival compared to administration of DLI to full donor chimeras. DLI also converted mixed chimeras to full chimeras without causing GVHD. The magnitude of the GVL effect was dependent on the level of major histocompatibility complex class I expression on recipient hematopoietic cells in mixed chimeras. Thus, the induction of mixed chimerism followed by delayed DLI provides an approach to inhibiting GVHD that optimizes GVL effects.
DNA vaccines encoding human immunodeficiency virus–1 glycoprotein 120 fusions with proinflammatory chemoattractants induce systemic and mucosal immune responses
Authors: Biragyn Arya , Belyakov Igor M. , Chow Yen-Hung , Dimitrov Dimiter S. , Berzofsky Jay A. , Kwak Larry W.
Published: October 2002

DNA immunizations with glycoprotein 120 (gp120) of human immunodeficiency virus–1 (HIV-1) usually require boosting with protein or viral vaccines to achieve optimal efficacy. Here, we demonstrate for the first time that mice immunized with DNA encoding gp120 fused with proinflammatory chemoattractants of immature dendritic cells, such as β-defensin 2, monocyte chemoattractant protein–3 (MCP-3/CCL7) or macrophage-derived chemokine (MDC/CCL22), elicited anti-gp120 antibodies with high titers of virus-neutralizing activity. The immunogenicity was further augmented with the use of chemokine fusion constructs with gp140, gp120 linked to the extracellular domain of gp41 via a 14–amino acid spacer peptide sequence. This construct elicited antibodies with more effective neutralizing activity than corresponding constructs expressing gp120. Responses were dependent on physical linkage with chemokine moiety, as no immunity was detected following immunization of mice with DNA encoding a free mixture of chemokine and gp120. Although the route of immunization was inoculation into skin, both systemic and mucosal CD8+ cytolytic immune responses were elicited in mice immunized with DNA expressing MCP-3 or β-defensin 2 fusion constructs. In contrast, no cytotoxic T lymphocyte activity (CTL) was detected in mice immunized with DNA encoding gp120 either alone or as fusion with MDC. Therefore, the potential for broad application of this approach lies in the induction of mucosal CTL and neutralizing antibodies to HIV-1 envelope, both key requirements for prevention of viral transmission and clearance of pathogenic HIV from mucosal reservoirs.
Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease
Authors: Muckian Clare , Fitzgerald Anthony , O'Neill Anne , O'Byrne Anna , Fitzgerald Desmond J. , Shields Denis C.
Published: October 2002

Although common genetic variants in platelet collagen receptors influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations studied were as follows: (1) a cross-sectional study of 703 acute coronary syndrome (ACS) patients with myocardial infarction (MI) and unstable angina, and (2) a prospective study of 924 Caucasian patients from the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4 carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P = .02) and stable angina (OR = 0.35, 95% CI = 0.16-0.74, P = .006). In the OPUS population, allele 4 again appeared protective against composite end points (death, MI, stroke, recurrent ischemia, and urgent rehospitalization) (relative risk [RR] = 0.41, 95% CI = 0.17-1.00). There were significant interactions between COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban, but appeared protective in placebo patients (RR = 0.53, 95% CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the product of which is a vessel-wall protein and platelet ligand, modulate the risk of coronary artery disease and could also modulate the response to antithrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.
Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox
Authors: Gorgun Gullu , Foss Francine
Published: October 2002

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10−6 to 10−10 M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R–targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery
Authors: Chakrabarti Suparno , Mautner Vivien , Osman Husam , Collingham Kathryn E. , Fegan Chris D. , Klapper Paul E. , Moss Paul A. H. , Milligan Donald W.
Published: October 2002

Adenovirus infections occur in 5% to 21% of patients following stem cell transplantation (SCT), with an associated mortality of up to 50%. However, a lack of prospective studies has hampered further developments in the understanding and management of this infection in the posttransplantation setting. We prospectively studied the incidence and outcome of adenovirus infections after SCT using preemptive screening and a policy of reduction or withdrawal of immunosuppressive therapy if the virus was isolated. The incidence of adenovirus infection was 19.7% (15 of 76), and the virus was isolated exclusively in recipients of T-cell–depleted grafts. Patients receiving 50 or 100 mg alemtuzumab in vivo were at the greatest risk of adenovirus infection (45% probability) regardless of donor type, and this was related to the slower lymphocyte recovery. Six (40%) of the 15 adenovirus-infected patients developed adenovirus disease. Severe lymphocytopenia (less than 300/μL) at the time of first detection of adenovirus was a major risk factor for development of adenovirus disease (P = .001). In addition, failure to reduce immunosuppression (P = .04) and a positive result of adenovirus polymerase chain reaction (PCR) in blood at diagnosis (P = .01) were both associated with fatal adenovirus disease. On the basis of this study, we recommend active surveillance for adenovirus infection in T-cell–depleted SCT and withdrawal or reduction of immunosuppressive treatment, if possible, in patients with adenovirus infection. Preemptive antiviral therapy is warranted for patients with severe lymphocytopenia or positive blood PCR, and in those in whom immunosuppressive therapy cannot be reduced.
Novel transcription factors in human CD34 antigen–positive hematopoietic cells
Authors: Gomes Ignatius , Sharma Tiffany T. , Edassery Seby , Fulton Noreen , Mar Brenton G. , Westbrook Carol A.
Published: October 2002

Transcription factors (TFs) and the regulatory proteins that control them play key roles in hematopoiesis, controlling basic processes of cell growth and differentiation; disruption of these processes may lead to leukemogenesis. Here we attempt to identify functionally novel and partially characterized TFs/regulatory proteins that are expressed in undifferentiated hematopoietic tissue. We surveyed our database of 15 970 genes/expressed sequence tags (ESTs) representing the normal human CD34+ cells transcriptosome (http://westsun.hema.uic.edu/cd34.html), using the UniGene annotation text descriptor, to identify genes with motifs consistent with transcriptional regulators; 285 genes were identified. We also extracted the human homologues of the TFs reported in the murine stem cell database (SCdb; http://stemcell.princeton.edu/), selecting an additional 45 genes/ESTs. An exhaustive literature search of each of these 330 unique genes was performed to determine if any had been previously reported and to obtain additional characterizing information. Of the resulting gene list, 106 were considered to be potential TFs. Overall, the transcriptional regulator dataset consists of 165 novel or poorly characterized genes, including 25 that appeared to be TFs. Among these novel and poorly characterized genes are a cell growth regulatory with ring finger domain protein (CGR19, Hs.59106), an RB-associated CRAB repressor (RBAK, Hs.7222), a death-associated transcription factor 1 (DATF1, Hs.155313), and a p38-interacting protein (P38IP, Hs. 171185). The identification of these novel and partially characterized potential transcriptional regulators adds a wealth of information to understanding the molecular aspects of hematopoiesis and hematopoietic disorders.
Engraftment potential of human fetal hematopoietic cells in NOD/SCID mice is not restricted to mitotically quiescent cells
Authors: Wilpshaar Jannine , Bhatia Mickie , Kanhai Humphrey H. H. , Breese Robert , Heilman Doug K. , Johnson Cynthia S. , Falkenburg J. H. Frederik , Srour Edward F.
Published: October 2002

During fetal development, there is a continued demand for large numbers of primitive and mature hematopoietic cells. This demand may require that all potential hematopoietic stem cells (HSCs) migrate effectively to emerging hematopoietic sites and subsequently contribute to blood cell production, regardless of their cell cycle status. We recently established that umbilical cord blood cells in the G1 phase of the cell cycle have a repopulating potential similar to cells in G0, suggesting that cycling prenatal and neonatal HSCs may have the same functional capabilities described for quiescent, but not cycling, cells from adult sources. To establish the relationship between cell cycle status and hematopoietic potential at early stages of human ontogeny, the in vivo engraftment potential of mitotically defined fetal liver (FL) and fetal bone marrow (FBM) cells were examined in NOD/SCID recipients. Following transplantation of the same numbers of G0, G1, or S/G2+M CD34+ cells from FL, equivalent percentages of recipient mice were chimeric (55%, 60%, and 60%, respectively). FBM-derived CD34+ cells in all phases of the cell cycle engrafted in conditioned recipients and sustained human hematopoiesis, albeit at lower levels than their FL-derived counterparts. Multilineage differentiation was evident in all transplanted mice independent of the source or cell cycle status of graft cells. In addition, levels of chimerism in mice transplanted with fetal blood–derived G0or G1 CD34+ lineage-depleted cells were similar. These results support the assertion that mitotically quiescent and cycling fetal hematopoietic cells contain marrow-repopulating stem cells capable of multilineage engraftment in NOD/SCID mouse recipients.
Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-xL is an essential survival protein of human myeloma cells
Authors: Derenne Sophie , Monia Brett , Dean Nicholas M. , Taylor Jennifer K. , Rapp Marie-Josée , Harousseau Jean-Luc , Bataille Régis , Amiot Martine
Published: October 2002

Multiple myeloma (MM) is a plasma cell malignancy that occurs mainly in bone marrow. As MM cells proliferate slowly, it would seem essential to find means of preventing their growth and accumulation inside bone marrow. The present study used an antisense strategy to elucidate the respective roles of Bcl-2, Bcl-xL, and Mcl-1 proteins in myeloma cell survival. Each antisense oligonucleotide (ASO; Bcl-2, Bcl-xL, or Mcl-1 ASO) introduced into human myeloma cell lines by electroporation induced a marked reduction in the level of the corresponding protein. Mcl-1 ASO triggers an important decrease of viability in all myeloma cell lines tested and in 2 primary myeloma cells, whereas neither Bcl-2 nor Bcl-xL ASO affected the viability of myeloma cells. The decrease of cell viability induced by Mcl-1 ASO treatment was associated with an induction of apoptosis that occurred through the disruption of mitochondrial membrane potential ΔΨm and the activation of executioner caspase-3. Furthermore, we have shown that interleukin 6 cannot prevent the Mcl-1 ASO-induced apoptosis. Finally, although Bcl-2 ASO treatment alone has no effect, it can sensitize myeloma cell lines to dexamethasone (Dex), whereas Bcl-xL ASO in combination with Dex still had no effect. As MM remains an incurable disease despite intensive chemotherapy, these results suggest that Mcl-1 antisense strategy rather than Bcl-2 antisense strategy could be of considerable importance in the treatment of MM.
Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice
Authors: Kogan Scott C. , Ward Jerrold M. , Anver Miriam R. , Berman Jules J. , Brayton Cory , Cardiff Robert D. , Carter John S. , de Coronado Sherri , Downing James R. , Fredrickson Torgny N. , Haines Diana C. , Harris Alan W. , Harris Nancy Lee , Hiai Hiroshi , Jaffe Elaine S. , MacLennan Ian C. M. , Pandolfi Pier Paolo , Pattengale Paul K. , Perkins Archibald S. , Simpson R. Mark , Tuttle Mark S. , Wong Joanne F. , Morse Herbert C.
Published: October 2002

The hematopathology subcommittee of the Mouse Models of Human Cancers Consortium recognized the need for a classification of murine hematopoietic neoplasms that would allow investigators to diagnose lesions as well-defined entities according to accepted criteria. Pathologists and investigators worked cooperatively to develop proposals for the classification of lymphoid and nonlymphoid hematopoietic neoplasms. It is proposed here that nonlymphoid hematopoietic neoplasms of mice be classified in 4 broad categories: nonlymphoid leukemias, nonlymphoid hematopoietic sarcomas, myeloid dysplasias, and myeloid proliferations (nonreactive). Criteria for diagnosis and subclassification of these lesions include peripheral blood findings, cytologic features of hematopoietic tissues, histopathology, immunophenotyping, genetic features, and clinical course. Differences between murine and human lesions are reflected in the terminology and methods used for classification. This classification will be of particular value to investigators seeking to develop, use, and communicate about mouse models of human hematopoietic neoplasms.
Nuclear magnetic resonance studies of mutations at the tetramerization region of human alpha spectrin
Authors: Park Sunghyouk , Johnson Michael E. , Fung Leslie W.-M.
Published: October 2002

Many spectrin mutations that destabilize tetramer formation and lead to hereditary hemolytic anemias are located at the N-terminal region of α-spectrin, with the Arg28 position considered to be a mutation hot spot. We have introduced mutations at positions 28 and 45 into a model peptide, Spα1-156, consisting of the first 156 residues in the N-terminal region of α-spectrin (αN). The association of these α-spectrin peptides that have single amino acid replacements with a β-spectrin model peptide, consisting of the C-terminal region of β-spectrin (βC), was determined, and structural changes due to amino acid replacements were monitored by nuclear magnetic resonance (NMR). We found evidence for similar and very localized structural changes in Spα1-156Arg45Thr and Spα1-156Arg45Ser, although these 2 mutant peptides associated with β-spectrin peptide with significantly differing affinities. The Spα1-156Arg28Ser peptide showed an affinity for the β-spectrin peptide comparable to that of Spα1-156Arg45Ser, but it exhibited substantial and widespread spectral changes. Our results suggest that both Arg45 replacements induce only minor structural perturbations in the first helix of Spα1-156, but the Arg28Ser replacement affects both the first helix and the following structural domain. Our results also indicate that the mechanism for reduced spectrin tetramerization is through mutation-induced changes in molecular recognition at the αβ-tetramerization site, rather than through conformational disruption, as has been suggested in prior literature.