bluuebunny/crossref_metadata_2025 huggingface dataset:
Hijikata Tatsumi: Plucking off the Darkness of the Flesh
Authors: Tatsuhiko Shibusawa
Published: July 2002

For the first time in English, we present many of Hijikata's aesthetic and poetic texts. These texts are put into context by Kurihara Nanako's introductory essay. The section includes an interview with Hijikata and a conversation between Hijikata and Japanese experimental theatre innovator Suzuki Tadashi.
Form Invariance and Implicit Parallelism
Authors: Vose Michael D. , Wright Alden H.
Published: July 2002

Holland's schema theorem (an inequality) may be viewed as an attempt to understand genetic search in terms of a coarse graining of the state space. Stephens and Waelbroeck developed that perspective, sharpening the schema theorem to an equality. Of particular interest is a “form invariance” of their equations; the form is unchanged by the degree of coarse graining. This paper establishes a similar form invariance for the more general model of Vose et al. and uses the attendant machinery as a springboard for an interpretation and discussion of implicit parallelism.
Symbiogenesis in Learning Classifier Systems
Authors: Tomlinson Andy , Bull Larry
Published: July 2002

Symbiosis is the phenomenon in which organisms of different species live together in close association, resulting in a raised level of fitness for one or more of the organisms. Symbiogenesis is the name given to the process by which symbiotic partners combine and unify, that is, become genetically linked, giving rise to new morphologies and physiologies evolutionarily more advanced than their constituents. The importance of this process in the evolution of complexity is now well established. Learning classifier systems are a machine learning technique that uses both evolutionary computing techniques and reinforcement learning to develop a population of cooperative rules to solve a given task.

In this article we examine the use of symbiogenesis within the classifier system rule base to improve their performance. Results show that incorporating simple rule linkage does not give any benefits. The concept of (temporal) encapsulation is then added to the symbiotic rules and shown to improve performance in ambiguous/non-Markov environments.
Books
Authors: Graedel Thomas E.
Published: July 2002

The Weight of Nations: Material Outflows from Industrial Economies, by E. Matthews, C. Amann, S. Bringezu, M. Fischer‐Kowalski, R. Kleijn, C. Ottke, E. Rodenburg, D. Rogich, H.Schütz, H. Schandl, and E. van der Voet

Heavy Metals: A Problem Solved?, edited by E.van der Voet, J. B. Guinée, and H. A. Udo de Haes
A Test Case of Moravcsik's “Liberal Intergovernmentalist” Approach to European Integration
Authors: Gillingham John
Published: July 2002

The responses to Andrew Moravcsik's article discuss the main substantive and methodological points raised in it. Although most of the respondents agree that Moravcsik has properly highlighted the importance of commercial concerns for de Gaulle's policy on European integration, they question the validity of his sharp separation between de Gaulle's political and economic goals for France. Several commentators argue that political and commercial concerns (including agricultural concerns) were closely intertwined in de Gaulle's vision of French grandeur.John Keeler brings up another crucial question: Was French agriculture really an obstacle to France's position in Europe? He argues that de Gaulle successfully supported and modernized French agriculture because he was convinced that this would contribute to France's geopolitical position in Europe and the Western world. In two longer commentaries, Jeffrey Vanke and Marc Trachtenberg raise questions about Moravcsik's methodology and use of sources. Both agree that Moravcsik draws on an impressive array of available materials concerning de Gaulle. But they both wonder whether a definitive account of de Gaulle's policies can be written when the documentary record is still incomplete, a point raised by the
TRADITIONIST-JURISPRUDENTS AND THE FRAMING OF ISLAMIC LAW
Authors: Melchert Christopher
Published: July 2002

The traditionist-jurisprudents (fuqahā' ashāb al-hadīth) of the earlier ninth century C.E. proposed that Islamic law be inferred from hadith, reports of what the Prophet, his leading Companions, and the Followers had said or done, without significant resort to reason. Contradictions among hadith reports they either resolved by means of isnād comparison or simply let stand, refusing to define the law by their own preferences. Their adversaries the rationalistic jurisprudents (ashāb al-ra'y) also used hadith, but far less extensively and without significant use of isnād comparison to sort out the sound from the unsound. In the later ninth century, rationalistic jurisprudents took up many of the forms formerly peculiar to the traditionist-jurisprudents, especially formal dependence on hadith and isnād comparison to sort the sound from the unsound. Traditionist-jurisprudents in turn accepted the need for separate expertise in legal reasoning besides hadith criticism. Although some developments took place independently of them, the history of Islamic law across the ninth century cannot be written without reference to the traditionist-jurisprudents and their strident advocacy of hadith.
Imagining Rabbits and Squirrels in the English Countryside
Authors: Kean Hilda
Published: July 2002

Drawing on contemporary coverage, particularly in The Field and Country Life, this article considers the construction of rabbits and squirrels as images of the past in England. By the 1930s, the red squirrel had become increasingly rare in the English countryside. Particularly in towns and suburbs, the population of the grey squirrel was growing rapidly. Those who saw themselves as the custodians of the countryside depicted the grey squirrel as a foreign force inimical to a mythical English way of life as epitomized by the red squirrel. In the post war period, the debate resurfaced about the nature of the countryside and who had a right to defend it. The focus then was upon the spread of myxomatosis from France, which was depicted as a foreign disease. Wild rabbits, who died in the thousands from this infection, became appropriated, as red squirrels before them, as symbols of a lyrical and ordered past in the countryside.
INTENSIVE FOOD SEARCHING IN HUMID PATCHES: ADAPTATION OF A MYRMICINE ANT TO ENVIRONMENTAL CONSTRAINTS
Authors: Durou  , Lauga  , Dejean
Published: July 2002

We tested if foragers of the ant Decamorium decem control the sinuosity of their food searching paths and their speed in order to concentrate their activity in areas of high prey density, humid patches of leaf-litter, during the dry season. In experimental situation I simulating the wet season (uniformly humid arenas) food searching paths were erratic and homing paths direct. In situation II simulating the dry season (dry arenas with a humidified disk) the sinuosity of the searching paths increased and the speed decreased when workers moved from the dry arenas to the humidified disks; homing paths were again direct. Thanks to comparisons with situation I, we argue that in situation II workers first oriented themselves toward the humidified disks (sinuosity significantly lower on the dry than on the wet arenas; non-significant difference for speed). Otherwise, we show that the intensive search on the humidified disks depends only on a decrease in speed (significantly lower on the humidified disks than on the wet arenas of situation I; non-significant difference for sinuosity), with workers switching from active searching to ambush when prey are absent.
SEXUAL CONFLICTS AND COPULATION PATTERNS IN POLYANDROUS BRONZE-WINGED JACANAS (METOPIDIUS INDICUS)
Authors: Butchart Stuart
Published: July 2002

Sperm competition was intense in polyandrous bronze-winged jacanas because females usually copulated with all their mates before laying a clutch for one of them. Females spent time with each male, but spent more time with the male that received the clutch ('receiver') in the immediate pre-laying and early laying periods, and overall gave more copulations to the receiver than to non-receivers. As receivers provided all the parental care, theory predicts that females should accede to male demands for copulations in order to assure them of their paternity so that they care for the clutch. Receivers may have destroyed clutches in which they gained a low share of the paternity. Conflicts occurred over the pattern of copulations because females were more likely to terminate male- than female-initiated sex events, and vice versa, and the proportion of sex events initiated by an individual and terminated by its mate was high for both males and females. Overall, a higher proportion of male than female initiations resulted in copulations. To test how these conflicts were resolved, I compared polyandrous groups and monogamous pairs. Male-initiated sex events tended to occur at higher rates and peaked later for polyandrous males than monogamous males. Males initiated sex events at higher rates than their mates, and the timing of copulations more closely matched that of male- than female-initiated sex events, suggesting that polyandrous females acceded to male demands for copulations. In monogamous pairs, copulations were less frequent (32 per clutch vs 97 in polyandrous groups). The duration and peak of the pattern of copulations more closely matched the pattern of initiations by females than males. However, both the timing of female-initiated sex events (mainly in the immediate pre-laying and early laying periods) and the high proportion of male initiations to which females responded suggested that copulations in monogamous pairs were also determined more by male preferences. Nonreceivers occasionally facilitated mate changes through tolerating intruder females and by territory adjustments (as described previously in wattled jacana Jacana jacana by Wrege & Emlen, 1998). Polyandrous females may have attempted to retain such males by giving them copulations and hence the opportunity for paternity (the 'sex for influence' hypothesis). Polyandrous females initiated sex events for a longer period than monogamous females, but did not do so at higher rates per male. Female-initiated sex events with non-receivers did not peak in the immediate pre-laying period (unlike those with receivers), and continued after the last egg had been fertilised. Copulations to guard against the loss of non-receiver mates may have been less important than copulations to ensure parental care by receivers, because all polyandrous females initiated sex events at higher rates with receivers and responded to a higher proportion of their initiations.
ON THE EVOLUTION OF LAKE BAIKAL AMPHIPODS
Authors: Kamaltynov Ravil Masalimovich
Published: July 2002

It is suggested that the ancestors of the Baikalian amphipods originated in Central Asian brackish-water basins in the Late Mesozoic, while the geological history of the Baikalian rift valley and subsequent Cenozoic glaciations influenced the evolution of the group. Il est suggere que les ancetres des amphipodes du lac Baikal ont leur origine dans les bassins d'eau saumatre d'Asie centrale a la fin du Mesozoique, bien que l'histoire geologique de la fosse du Baikal et les glaciations cenozoiques subsequentes aient influe sur l'evolution du groupe.
Friendship on the Margins: Jewish Social Relations in Imperial Germany
Authors: Kaplan Marion
Published: July 2002

Historians who look at the stark contrast between the spectacular successes of Jews in late nineteenth-century Germany and their horrific end in the Holocaust only a few decades later continue to argue about the relative success or failure of Jewish integration into German society. Were Germany's 600, 000 Jews — only 1 percent of the population — fully integrated or not? Did they have non-Jewish friends or not? Were they accepted or were they strangers in their own land?
Lacustrine mineral facies and implications for estimation of palaeoenvironmental parameters: Neogene intervolcanic Pelitçik Basin (Galatean Volcanic Province), Turkey
Authors: Süzen M. L. , Türkmenoğlu A. G.
Published: July 2002

The mineralogy of the Neogene lacustrine facies of Pelitçik basin was investigated for the purpose of deriving the palaeoenvironmental parameters of this intervolcanic basin. The laboratory studies indicate that dolomite and K-feldspar are the major non-clay minerals in the study area, where plagioclase, analcime, fibrous zeolite and quartz are the minor constituents. Dolomites are found to be non-stoichiometric in chemistry. The clay fraction of the lacustrine facies is composed mainly of dioctahedral smectites. The smectites are rich in Al-Fe indicating a detrital origin. Illite comprises a minor contribution to the clay fraction, where chlorite and kaolinite are found in trace amounts. Based on dolomite stoichiometry and the mineral paragenesis found in the Pelitçik basin, the depositional conditions are suggested to have been a shallow, quiet, perennial lacustrine environment with fresh to slightly saline and slightly alkaline water chemistry. In addition, based on geological and mineralogical constraints, it is suggested that the water chemistry fluctuated during the deposition of the Pazar formation and the lake began its evolution with a hydrologically closed system and completed its evolution with a hydrologically open system.
Retarded illite crystallinity caused by stressinduced sub-grain boundaries in illite
Authors: Giorgetti G. , Memmi I. , Peacor D. R.
Published: July 2002

An XRD-TEM study was carried out on low-grade metapelites (Transantarctic Mountains) to determine the cause of apparent inconsistences in grade as determined by IC and independent geologic relations. The illite crystallinity (IC) data indicate that the three units investigated (BT, RBT, MS) were affected by very low- (IC = 0.24°Δ2θ in BT) to low-grade metamorphism (0.19°Δ2θ in MS). In all three samples, mica crystals are of a size typical of the epizone, but the mean size increases from BT to RBT and MS, due to the increasing strain features from BT to MS. These results indicate that strain-induced reduction in crystal size was retained in BT samples (with anomalously high IC values). Microtextures in RBT and MS (with smaller IC) samples suggest a recovery of sub-grain boundaries. A decrease in crystal size may occur with increasing grade where strain rates are high relative to the rate of recrystallization.
Mixed-layer mica-chlorite in very low-grade metaclastites from the Malàguide Complex (Betic Cordilleras, Spain)
Authors: Ruiz Cruz M. D.
Published: July 2002

Mixed-layered phyllosilicates with composition intermediate between mica and chlorite were identified in very low-grade metaclastites from the Malàguide Complex (Betic Cordilleras, Spain), and studied by X-ray diffraction, and transmission and analytical electron microscopy. They occur both as small grains in the rock matrix, and associated with muscovitechlorite stacks. Transmission electron microscope observations revealed a transition from chlorite to ordered 1:1 interstratifications through complex 1:2 and 1:3 interstratifications. Analytical electron microscopy data indicate a composition slightly different from the sum of discrete trioctahedral chlorite and dioctahedral mica. The types of layer transitions suggest that mixed-layer formation included two main processes: (1) the replacement of a brucite sheet by a cation sheet in the chlorite structure; and (2) the precipitation of mica-like layers between the chlorite layers. The strongest diffraction lines in oriented X-ray patterns are: 12.60 Å (002), 7.98 Å (003), 4.82 Å (005) and 3.48 Å (007).
Texture and orientation of kaolin in coatings
Authors: Elton N. J. , Gate L. F. , Hooper J. J.
Published: July 2002

X-ray diffraction (XRD), infra red (IR) spectroscopy, gloss goniophotometry and stylus profilometry were used to investigate the alignment of kaolinite applied as a thin coating on a polyester film substrate. The principles and applicability of the analytical methods are reviewed and discussed in the context of a kaolinite coating. X-ray diffraction and transmission IR were used to measure kaolinite misalignment and orientation distribution in the coating. Transmission IR measures the coating bulk; XRD data are surface biased, but contain contributions from the bulk. Attenuated total reflectance-IR (ATR-IR) provides a direct measure of kaolinite alignment within ~1 µm of the coating surface and also allows an assessment of surface smoothness. Gloss goniophotometry and contact profilometry measure surface microroughness and macroroughness, respectively, rather than kaolinite particle orientation. However, the properties of roughness and orientation are related. Bulk and surface texture are not necessarily correlated and a combined approach using both bulk and surface sensitive techniques is required for a full understanding of coating structure.
Interpretation of the infrared spectrum of the -clays: application to the evaluation of the layer charge
Authors: Petit S. , Righi D. , Madejová J. , Decarreau A.
Published: July 2002

The IR spectra of-saturated smectites were examined in terms of their charge characteristics. The υ4band near 1440 cm-1, observed in the DRIFTS spectra (obtained without use of a KBr matrix), was assigned to the vibrations ofions compensating the negative charge of the clays. When KBr was used as a diluting matrix, the υ4band was located at 1400 and/or 1440 cm-1. The band at 1400 cm-1, related to NH4Br, originated from the replacement ofin the clay by K+from the KBr. For swelling clay minerals this band indicates that layers have permanent low charge density and/or variable charge. For non-swelling clay minerals, the 1400 cm-1band characterizes the presence of variable charges only. The υ4band at 1440 cm-1suggests thatin the clay was not replaced by K+from KBr and remains in the interlayer space of the clay minerals. This absorption is due tocompensating only permanent charge in the interlayers, or part of the interlayers with a high charge density. The presence of both bands at 1400 cm-1and 1440 cm-1in the IR spectrum suggests that the clays studied have a heterogeneous interlayer charge.
Chemistry of Hf-rich zircons from the Laoshan I- and A-type granites, Eastern China
Authors: Wang R. C. , Zhao G. T. , Lu J. J. , Chen X. M. , Xu S. J. , Wang D. Z.
Published: July 2002

Zircon commonly occurs as one of important accessory HFSE-bearing minerals in A-type granite. A detailed electron microprobe study was carried out on zircon from the Laoshan complex, Eastern China, which is composed of I- and A-type granites. Zircon from the I-type rocks is relatively poor in trace elements (HfO2<2 wt.%, UO2, ThO2 and Y2O3 <1 wt.%), but that from the A-type rocks is richer in Hf, U, Th and Y. Hafnian zircon with a HfO2 content of up to 12.37 wt.% was found in the arfvedsonite granite, which is considered the most evolved facies in the A-type suite. Enrichment in Hf is generally observed at the rims of zircon crystals relative to the cores. The Hf enrichment in zircon, and the association of exotic REE- and HFSE-bearing minerals are linked to hydrothermal activity, suggesting that during the last stage of crystallization of the A-type magma, fluids enriched in REE, HFSE, F−, CO32− and PO43− were released.
Rengeite, Sr4ZrTi4Si4O22, a new mineral, the Sr-Zr analogue of perrierite from the Itoigawa-Ohmi district, Niigata Prefecture, central Japan
Authors: Miyajima H. , Matsubara S. , Miyawaki R. , Yokoyama K. , Hirokawa K.
Published: July 2002

Rengeite, Sr4ZrTi4Si4O22, is a new member of the perrierite–chevkinite group found in the jades from the Itoigawa-Ohmi district, central Japan. It is monoclinic,P21/a,a= 13.97(1),b= 5.675(7),c= 11.98(1)Å, β = 114.26(8)°,V= 866 Å3andZ= 2. The six strongest lines in the X-ray powder diffraction pattern are 3.12 (s) (40-3), 3.05 (vvs) (31-3), 2.99 (vs) (311), 2.84 (s) (020), 2.74 (s) (004), 2.20 (s) (31-5). Electron microprobe analysis gave SiO222.58, TiO229.88, ZrO29.49, Nb2O50.24, Ta2O50.07, Al2O30.20, FeO 0.10, CaO 0.43, SrO 34.32, BaO 0.13, La2O30.00, Ce2O30.38, Pr2O30.10, Nd2O30.29, Sm2O30.04, total 98.25 wt.%, corresponding to (Sr3.62Ca0.08Ce0.03Nd0.02Ba0.01Pr0.01)∑3.76(Zr0.84Ti0.09Al0.04Fe0.02Nb0.02)∑1.01Ti4.00Si4.11O22on the basis of O = 22. The unitcell parameters and chemical composition imply that rengeite is the Sr and Zr-analogue of perrierite or high-β analogue of strontiochevkinite. It is transparent, dark brown with adamantine lustre. Its streak is pale greenish brown, and no cleavage was observed. The hardness is VHN100606–698 kg mm−2(Mohs 5–5.5). The calculated density is 4.12 g cm−3. It is strongly pleochroic from pale green to pale greenish brown where theREEcontents are <1 wt.% and pale violet to greenish brown where theREEcontents are between 3 and 10 wt.%. It occurs as anhedral grains in close association with titanite, zircon and tausonite in a pebble of blue titanian omphacite-jadeite rock from the seashore of Oyashirazu, Ohmi Town, in a boulder of lavender-coloured Ti-bearing jadeitite from the bed of the Kotaki-gawa river, Itoigawa City, and in a boulder of green jade from the bed of the Hime-kawa river, Itoigawa City, Niigata Prefecture, central Japan. Rengeite is considered to have crystallized by interaction between pre-existing minerals (rutile, anatase, titanite and zircon) and Sr-rich metamorphic fluid during later stage activity of high-P/Tmetamorphism. The name is for Mt. Renge near the locality and the Renge metamorphic belt where jadeitite deposits are found.
Melt inclusions in granitoids of the Timna Igneous Complex, Southern Israel
Authors: Vapnik Ye.
Published: July 2002

High temperature microthermometry and Scanning Electron Microprobe (SEM) analyses were used to study natural magmatic remnants in quartz crystals in granitoids from the Timna Igneous Complex, southern Israel, and to constrain physicochemical parameters during their crystallization. For the porphyritic granite, alkali granite and quartz monzodiorite, liquidus temperatures are 710–770, 770–830 and 770–840°C, respectively; solidus temperatures are 690–770, 710–790 and 770°C, respectively. Pressures during crystallization and water content in the magmas were determined using the phase diagram of the modal granite system. The determined P-T-conditions are typical for water-saturated granitoid magmas (>4–8 wt.%) generated and crystallized at a shallow crustal level.

SEM data on melt inclusions support conclusions of previous investigations on two types of granitoid magmas exposed in the Timna Igneous Complex: the porphyritic and alkali granites. Different trends of crystallization are proposed for these granites. Crystallization of the porphyritic granite started with cotectic crystallization of plagioclase and terminated in residual K-feldspar-rich crystallization; crystallization of the alkali granite took place at higher temperatures, starting with K-rich alkali-feldspar crystallization and terminating in residual Na-rich eutectic crystallization.

Parameters not available from other sources — temperature and pressure of the liquidus and solidus stages, water content, trends of crystallization — were obtained for the porphyritic and alkali granites.
Subsolidus rubidium-dominant feldspar from the Morrua pegmatite, Mozambique:
paragenesis and composition
Authors: Teertstra D. K. , Černý P. , Hawthorne F. C.
Published: July 2002

At the Morrua pegmatite, Mozambique, alkali feldspar has replaced pollucite
under low-temperature (250–150°C) hydrothermal conditions. Fluids invading a
fracture system in pollucite formed round granular aggregates of (K-Rb)-feldspar
in three stages: (1) a compositionally heterogeneous core of the feldspar cluster
(+cookeite ± apatite) with 7–20 mol.%
RbAlSi3O8, grading outward into a
Rb-dominant feldspar with 66 mol.%
RbAlSi3O8 (20 wt.%
Rb2O); (2) an intermediate layer of non-porous,
inclusion-free, end-member K-feldspar; (3) an outer layer of porous end-member
K-feldspar. Feldspars of all three stages seem to be monoclinic and disordered,
with metastable sanidine structure. Zoning in K/Rb, preserved on a fine scale, was
formed during growth at a temperature too low for subsequent alkali-cation
diffusion or (Al,Si)-ordering.
Silvialite, a new sulfate-dominant member of the scapolite group with an Al-Si composition near the 14/m–P42/nphase transition
Authors: Teertstra D. K. , Schindler M. , Sherriff B. L. , Hawthorne F. C.
Published: July 2002

Silvialite, ideally Ca4Al6Si6O24SO4, is tetragonal,I4/m, Z = 2, witha= 12.160(3),c= 7.560(1) Å,V= 1117.9(8) Å3,c:a= 0.6217:1, ω = 1.583, ε = 1.558 (uniaxial negative), Dm= 2.75 g/cm3, Dcalc= 2.769 g/cm3and H (Mohs) = 5.5. It is transparent and slightly yellow, has a good {100} cleavage, chonchoidal fracture, white streak and a vitreous lustre. It occurs in upper-mantle garnet-granulite xenoliths hosted by olivine nephelinite, from McBride Province, North Queensland, Australia. The empirical formula, derived from electron-microprobe analysis, is (Na1.06Ca2.86)(Al4.87Si7.13)O24[(SO4)0.57(CO3)0.41]. Crystal-structure refinement shows disordered carbonate and sulfate groups along the fourfold axis. Silvialite is a primary cumulate phase precipitated from alkali basalt at 900–1000°C and 8–12 kbar under highfSO2andfO2. The name silvialite, currently used in literature to describe the sulfate analogue of meionite, was suggested by Brauns (1914).
Isotopic and geochemical investigation of a carbonatite-syenite-phonolite diatreme, West Eifel (Germany)
Authors: Riley T. R. , Bailey D. K. , Harmer R. E. , Liebsch H. , Lloyd F. E. , Palmer M. R.
Published: July 2002

The Rockeskyll complex in the north, central part of the Quaternary West Eifel volcanic field encapsulates an association of carbonatite, nephelinite and phonolite. The volcanic complex is dominated by three eruptive centres, which are distinct in their magma chemistry and their mode of emplacement. The Auf Dickel diatreme forms one centre and has erupted the only known carbonatite in the West Eifel, along with a broad range of alkaline rock types. Extrusive carbonatitic volcanism is represented by spheroidal autoliths, which preserve an equilibrium assemblage. The diatreme has also erupted xenoliths of calcite-bearing feldspathoidal syenite, phonolite and sanidine and clinopyroxene megacrysts, which are interpreted as fragments of a sub-volcanic complex. The carbonate phase of volcanism has several manifestations; extrusive lapilli, recrystallized ashes and calcite-bearing syenites, fragmented during diatreme emplacement.

A petrogenetic link between carbonatites and alkali mafic magmas is confirmed from Sr and Nd isotope systematics, and an upper mantle origin for the felsic rocks is suggested. The chemistry and mineralogy of mantle xenoliths erupted throughout the West Eifel indicate enrichment in those elements incompatible in the mantle. In addition, the evidence from trace element signatures and melts trapped as glasses support interaction between depleted mantle and small volume carbonate and felsic melts. This close association between carbonate and felsic melts in the mantle is mirrored in the surface eruptives of Auf Dickel and at numerous alkaline-carbonatite provinces worldwide.
Antigenicity of putative phospholipid membrane-binding residues in factor VIII
Authors: Barrow Rachel T. , Healey John F. , Jacquemin Marc G. , Saint-Remy Jean-Marie R. , Lollar Pete
Published: July 2002

Most inhibitory antibodies to human factor VIII (fVIII) bind to epitopes in the A2, ap-A3, or C2 domains. The anticoagulant action of antibodies to the C2 domain is due to inhibition of binding of fVIII to phospholipid. The x-ray structure of the human fVIII C2 domain shows a putative hydrophobic, 3-prong, phospholipid membrane-binding site consisting of Met2199/Phe2200, Val2223, and Leu2251/Leu2252. Additionally, Lys2227, near Val2223, is part of a ring of positively charged residues that may contribute to electrostatic interaction of fVIII with negatively charged phosphatidylserine. In this study, 8 active mutants of human fVIII (Met2199Ile, Leu2252Phe, Phe2200Leu, Val2223Ala, Lys2227Glu, Met2199Ile/Phe2200Leu, Val2223Ala/Lys2227Glu, and Met2199Ile/Phe2200Leu/Val2223Ala/Lys2227Glu), which were constructed on the basis of differences between human, porcine, murine, and canine fVIII at proposed phospholipid binding sites, were expressed. The antigenicity of the mutants toward 5 C2-specific polyclonal human antibodies was measured by using the Bethesda assay. A human monoclonal anti-C2 antibody, BO2C11, and a murine C2-specific monoclonal antibody, NMC VIII-5, were also included in the analysis. In comparison with wild-type, B-domainless fVIII, the Met2199Ile, Phe2200Leu, and Leu2252 single mutants had lower antigenicity toward most of the inhibitors. In contrast, the Val2223Ala and Lys2227Glu mutants usually showed increased antigenicity. These results suggest that C2 inhibitors frequently target the Met2199/Phe2200 and Leu2251/Leu2252 β-hairpins and are consistent with the hypothesis that these residues participate in binding to phospholipid membranes. In contrast, Val2223 and Lys2227 may oppose antibody binding sterically or through stabilization of a low-affinity membrane-binding conformation of the C2 domain.
Initiation of polyoma virus origin-dependent DNA replication through STAT5 activation by human granulocyte-macrophage colony-stimulating factor
Authors: Watanabe Sumiko , Zeng Rong , Aoki Yutaka , Itoh Tohru , Arai Ken-ichi
Published: July 2002

Several lines of evidence indicate that transcriptional activation is coupled with DNA replication initiation, but the nature of initiation of DNA replication in mammalian cells is unclear. Polyoma virus replicon is an excellent system to analyze the initiation of DNA replication in murine cells because its replication requires an enhancer, and all components of replication machinery, except for DNA helicase large T antigen, are supplied by host cells. This system was used to examine the role of signal transducer and activator of transcription (STAT5) in replication initiation of polyoma replicon in the mouse lymphoid cell line BA/F3. The plasmid with tandem repeats of consensus STAT5 binding sites followed by polyoma replication origin was replicated by stimulation with human granulocyte-macrophage colony-stimulating factor (hGM-CSF) in the presence of polyoma large T antigen in BA/F3 cells. Mutation analysis of the hGM-CSF receptor β subunit revealed that only the box1 region is essential, and the C-terminal tyrosine residues are dispensable for the activity. Addition of the tyrosine kinase inhibitor genistein suppressed this replication without affecting transcriptional activation of STAT5. Because deletion analysis of STAT5 indicates the importance of the C-terminal transcriptional activation domain of STAT5 for the initiation of replication, the role of this region in the activation of replication was examined with a GAL4–STAT5 fusion protein. GAL4–STAT5 activated replication of the plasmid containing tandem repeats of GAL4 binding sites and polyoma replication origin in BA/F3 cells. Mutation analysis of GAL4–STAT5 indicated that multiple serine residues coordinately have a role in activating replication. This is the first direct evidence indicating the potential involvement of STAT5 in replication.
Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients
Authors: Kay Neil E. , Leong Tracy L. , Bone Nancy , Vesole David H. , Greipp Philip R. , Van Ness Brian , Oken Martin M. , Kyle Robert A.
Published: July 2002

Previously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4+or CD19+ cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3+, CD4+, CD8+, CD19+, and CD4+ subset cell levels were all positively associated with survival (P = .0087 toP < .0001). A multivariate analysis incorporating CD4+ and CD19+ cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19+ blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P < .0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8+, which was greater than CD4+, which was greater than CD19+. This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19+ blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.
Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study
Authors: List Alan F. , Kopecky Kenneth J. , Willman Cheryl L. , Head David R. , Persons Diane L. , Slovak Marilyn L. , Dorr Robert , Karanes Chatchada , Hynes Harry E. , Doroshow James H. , Shurafa Muhammad , Appelbaum Frederick R.
Published: July 2002

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)–mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%,P = .0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P = .14), relapse-free survival (34% versus 9% at 2 years,P = .031) and overall survival (22% versus 12%,P = .046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P = .0089) and daunorubicinol (P < .0001) were significantly higher in CsA-treated patients. Survival (P = .0003) and induction response (P = .028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML.
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients
Authors: Barlogie Bart , Desikan Raman , Eddlemon Paul , Spencer Trey , Zeldis Jerome , Munshi Nikhil , Badros Ashrof , Zangari Maurizio , Anaissie Elias , Epstein Joshua , Shaughnessy John , Ayers Dan , Spoon Dan , Tricot Guido
Published: July 2002

This report of a phase 2 trial of thalidomide (THAL) (200 mg/d; 200 mg increment every 2 weeks to 800 mg) for 169 patients with advanced myeloma (MM) (abnormal cytogenetics (CG), 67%; prior autotransplant, 76%) extends earlier results in 84 patients. A 25% myeloma protein reduction was obtained in 37% of patients (50% reduction in 30% of patients; near-complete or complete remission in 14%) and was more frequent with low plasma cell labeling index (PCLI) (below 0.5%) and normal CG. Two-year event-free and overall survival rates were 20% ± 6% and 48% ± 6%, respectively, and these were superior with normal CG, PCLI of less than 0.5%, and β2-microglobulin of 3 mg/L. Response rates were higher and survival was longer especially in high-risk patients given more than 42 g THAL in 3 months (median cumulative dose) (landmark analysis); this supports a THAL dose-response effect in advanced MM.
Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation
Authors: Narayanasami Uma , Kanteti Rajani , Morelli Julie , Klekar Alanna , Al-Olama Asma , Keating Claire , O'Connor Colleen , Berkman Eugene , Erban John K. , Sprague Kellie A. , Miller Kenneth B. , Schenkein David P.
Published: July 2002

Peripheral blood cell (PBC) rescue has become the mainstay for autologous transplantation in patients with lymphoma, multiple myeloma, and solid tumors. Different methods of hematopoietic progenitor cell (HPC) mobilization are in use without an established standard. Forty-seven patients with relapsed or refractory lymphoma received salvage chemotherapy and were randomized to have HPC mobilization using filgrastim [granulocyte–colony-stimulating factor (G-CSF)] alone for 4 days at 10 μg/kg per day (arm A) or cyclophosphamide (5 g/m2) and G-CSF at 10 μg/kg per day until hematologic recovery (arm B). Engraftment and ease of PBC collection were primary outcomes. All patients underwent the same high-dose chemotherapy followed by reinfusion of PBCs. There were no differences in median time to neutrophil engraftment (11 days in both arms;P = .5) or platelet engraftment (14 days in arm A, 13 days in arm B; P = .35). Combined chemotherapy and G-CSF resulted in higher CD34+ cell collection than G-CSF alone (median, 7.2 vs 2.5 × 106 cells/kg;P = .004), but this did not impact engraftment. No differences were found in other PBC harvest outcomes or resource utilization measures. A high degree of tumor contamination, as studied by consensus CDR3 polymerase chain reaction of the mobilized PBCs, was present in both arms (92% in arm A vs 90% in arm B;P = 1). No differences were found in overall survival or progression-free survival at a median follow-up of 21 months. This randomized trial provides clinical evidence that the use of G-CSF alone is adequate for HPC mobilization, even in heavily pretreated patients with relapsed lymphoma.
Preferential loss of maternal 9p alleles in childhood acute lymphoblastic leukemia
Authors: Morison Ian M. , Ellis Lana M. , Teague Lochie R. , Reeve Anthony E.
Published: July 2002

Germ-line events, such as paternal mutation or genomic imprinting, contribute to the early onset of childhood cancers such as retinoblastoma, Wilms tumors, and neuroblastoma. Given the high frequency of deletion involving chromosome 9p in childhood acute lymphoblastic leukemia (ALL), this study investigated whether 9p deletion might reflect preexisting germ-line gene inactivation. To do this the parental origin of deletion was determined in 10 cases of ALL with 9p21 loss of heterozygosity. Of these cases, 9 showed loss of the maternally derived allele, suggesting that a germ-line event involving a 9p gene may play a role in the onset of childhood ALL.
Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils
Authors: Maianski Nikolai A. , Mul Frederik P. J. , van Buul Jaap D. , Roos Dirk , Kuijpers Taco W.
Published: July 2002

The exact mechanism of apoptosis in neutrophils (PMNs) and the explanation for the antiapoptotic effect of granulocyte colony-stimulating factor (G-CSF) in PMNs are unclear. Using specific fluorescent mitochondrial staining, immunofluorescent confocal microscopy, Western blotting, and flow cytometry, this study found that PMNs possess an unexpectedly large number of mitochondria, which are involved in apoptosis. Spontaneous PMN apoptosis was associated with translocation of the Bcl-2–like protein Bax to the mitochondria and subsequent caspase-3 activation, but not with changes in the expression of Bax. G-CSF delayed PMN apoptosis and prevented both associated events. These G-CSF effects were inhibited by cycloheximide. The general caspase inhibitor z-Val-Ala-DL-Asp-fluoromethylketone (zVAD-fmk) prevented caspase-3 activation and apoptosis in PMNs, but not Bax redistribution. PMN-derived cytoplasts, which lack a nucleus, granules, and mitochondria, spontaneously underwent caspase-3 activation and apoptosis (phosphatidylserine exposure), without Bax redistribution. zVAD-fmk inhibited both caspase-3 activation and phosphatidylserine exposure in cultured cytoplasts. Yet, G-CSF prevented neither caspase-3 activation nor apoptosis in cytoplasts, confirming the need for protein synthesis in the G-CSF effects. These data demonstrate that (at least) 2 routes regulate PMN apoptosis: one via Bax-to-mitochondria translocation and a second mitochondria-independent pathway, both linked to caspase-3 activation. Moreover, G-CSF exerts its antiapoptotic effect in the first, that is, mitochondria-dependent, route and has no impact on the second.
End‐tidal Carbon Dioxide Monitoring during Procedural Sedation
Authors: Miner James R. , Heegaard William , Plummer David
Published: July 2002

Abstract.Objective:To prospectively determine whether end‐tidal carbon dioxide (ETCO2) monitors can detect respiratory depression (RD) and the level of sedation in emergency department (ED) patients undergoing procedural sedation (PS).

Methods:This was a prospective observational study conducted in an urban county hospital of adult patients undergoing PS. Patients were monitored for vital signs, depth of sedation per the physician by the Observer's Assessment of Alertness/Sedation scale (OAA/S), pulse oximetry, and nasal‐sample ETCO2during PS. Respiratory depression was defined as an oxygen saturation <90%, an ETCO2>50 mm Hg, or an absent ETCO2waveform at any time during the procedure. The physician also determined whether protective airway reflexes were lost during the procedure and assisted ventilation was required, or whether there were any other complications. Rates of RD were compared with the physician assessment of airway loss and between agents using chi‐square statistics. Spearman's rho analysis was used to determine whether there was a correlation between ETCO2and the OAA/S score.

Results:Seventy‐four patients were enrolled in the study. Forty (54.1%) received methohexital, 21 (28.4%) received propofol, ten (13.5%) received fentanyl and midazolam, and three (4.1%) received etomidate. Respiratory depression was seen in 33 (44.6%) patients, including 47.5% of patients receiving methohexital, 19% receiving propofol (p = 0.008), 80% receiving fentanyl and midazolam, and 66.6% receiving etomidate. No correlation between OAA/S and ETCO2was detected. Eleven (14.9%) patients required assisted ventilation at some point during the procedure, all of whom met the criteria for RD. Pulse oximetry detected 11 of the 33 patients with RD. Post‐hoc analysis revealed that all patients with RD had an ETCO2>50 mm Hg, an absent waveform, or an absolute change from baseline in ETCO2>10 mm Hg.

Conclusions:There was no correlation between ETCO2and the OAA/S score. Using the criteria of an ETCO2>50 mm Hg, an absolute change >10 mm Hg, or an absent waveform may detect subclinical RD not detected by pulse oximetry alone. The ETCO2may add to the safety of PS by quickly detecting hypoventilation during PS in the ED.
Influence of Unrecognized Molecular Heterogeneity on Randomized Clinical Trials
Authors: Betensky Rebecca A. , Louis David N. , Gregory Cairncross J.
Published: July 2002

PURPOSE: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients’ outcomes.

PATIENTS AND METHODS: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase II studies.

RESULTS: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase II trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders.

CONCLUSION: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancer.
Successful Treatment of Mogamulizumab-Associated Rash With Upadacitinib
Authors: Martín-Torregrosa Daniel , Torres-Navarro Ignacio , Mansilla-Polo Miguel , Navarro-Blanco Fernando , de Unamuno-Bustos Blanca , Cózar Vicent Martínez I. , Botella-Estrada Rafael
Published: December 2024

This case report describes 2 older patients with refractory mogamulizumab-associated rash successfully treated with upadacitinib.