bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sloop ISA and the SMOK toolkit
Authors: Dugan B. , Zahorjan J.
Published: October 2002

Sloop-SMOK is a toolkit designed to improve the student design experience in a machine organization course taken by undergraduates in their first year as computer science majors. Students in this course have had some programming experience, and may have taken a one-quarter digital design course. Before Sloop-SMOK, assignments in this course were typically assembly language program implementations of functions related to architecture. The major goals in building Sloop-SMOK were to improve the relevance of homework assignments to machine organization and to emphasize some fundamental concepts of modern processors not easily addressed previously.Sloop-SMOK has two components. The Sloop is a machine architecture designed to allow implementation of a modern version of the 6502, the processor used in one of the early Atari game stations. The Sloop defines a RISC ISA and a set of on-the-fly translations from the original 6502 CISC ISA into Sloop instructions. The Sloop Machine Organization Kit (SMOK) is a general-purpose software machine organization simulator. The components of a SMOK model are at the level of detail found in typical machine organization texts: ALUs, register files, logic gates, and the like. SMOK provides a graphical interface to construct and debug models.As homework assignments, students use SMOK to build Sloop machines that successfully run most original 6502 games. Extensions to SMOK provide specific help with these Sloop models. Of particular importance is support for debugging: SMOK, when used to build a Sloop machine, runs a software 6502 simulator and compares the behavior of the student's Sloop machine against the simulator on a per-memory-operation basis. This feature simplifies debugging of Sloop machine organization by raising an error at the earliest cycle at which the student's machine is known to deviate from correct behavior.Sloop-SMOK, including downloadable software, documentation, and course assignments, is available at http://www.cs.washington.edu/software/SMOK
Secure program partitioning
Authors: Zdancewic Steve , Zheng Lantian , Nystrom Nathaniel , Myers Andrew C.
Published: October 2002

This paper presents secure program partitioning, a language-based technique for protecting confidential data during computation in distributed systems containing mutually untrusted hosts. Confidentiality and integrity policies can be expressed by annotating programs with security types that constrain information flow; these programs can then be partitioned automatically to run securely on heterogeneously trusted hosts. The resulting communicating subprograms collectively implement the original program, yet the system as a whole satisfies the security requirements of participating principals without requiring a universally trusted host machine. The experience in applying this methodology and the performance of the resulting distributed code suggest that this is a promising way to obtain secure distributed computation.
Graphical modeling and animation of ductile fracture
Authors: O'Brien James F. , Bargteil Adam W. , Hodgins Jessica K.
Published: October 2002

In this paper, we describe a method for realistically animating ductile fracture in common solid materials such as plastics and metals. The effects that characterize ductile fracture occur due to interaction between plastic yielding and the fracture process. By modeling this interaction, our ductile fracture method can generate realistic motion for a much wider range of materials than could be realized with a purely brittle model. This method directly extends our prior work on brittle fracture [O'Brien and Hodgins, SIGGRAPH 99]. We show that adapting that method to ductile as well as brittle materials requires only a simple to implement modification that is computationally inexpensive. This paper describes this modification and presents results demonstrating some of the effects that may be realized with it.
Integrated learning for interactive synthetic characters
Authors: Blumberg Bruce , Downie Marc , Ivanov Yuri , Berlin Matt , Johnson Michael Patrick , Tomlinson Bill
Published: October 2002

The ability to learn is a potentially compelling and important quality for interactive synthetic characters. To that end, we describe a practical approach to real-time learning for synthetic characters. Our implementation is grounded in the techniques of reinforcement learning and informed by insights from animal training. It simplifies the learning task for characters by (a) enabling them to take advantage of predictable regularities in their world, (b) allowing them to make maximal use of any supervisory signals, and (c) making them easy to train by humans.We built an autonomous animated dog that can be trained with a technique used to train real dogs called "clicker training". Capabilities demonstrated include being trained to recognize and use acoustic patterns as cues for actions, as well as to synthesize new actions from novel paths through its motion space.A key contribution of this paper is to demonstrate that by addressing the three problems of state, action, and state-action space discovery at the same time, the solution for each becomes easier. Finally, we articulate heuristics and design principles that make learning practical for synthetic characters.
A lighting reproduction approach to live-action compositing
Authors: Debevec Paul , Wenger Andreas , Tchou Chris , Gardner Andrew , Waese Jamie , Hawkins Tim
Published: October 2002

We describe a process for compositing a live performance of an actor into a virtual set wherein the actor is consistently illuminated by the virtual environment. The Light Stage used in this work is a two-meter sphere of inward-pointing RGB light emitting diodes focused on the actor, where each light can be set to an arbitrary color and intensity to replicate a real-world or virtual lighting environment. We implement a digital two-camera infrared matting system to composite the actor into the background plate of the environment without affecting the visible-spectrum illumination on the actor. The color reponse of the system is calibrated to produce correct color renditions of the actor as illuminated by the environment. We demonstrate moving-camera composites of actors into real-world environments and virtual sets such that the actor is properly illuminated by the environment into which they are composited.
Shader-driven compilation of rendering assets
Authors: Lalonde Paul , Schenk Eric
Published: October 2002

Rendering performance of consumer graphics hardware benefits from pre-processing geometric data into a form targeted to the underlying API and hardware. The various elements of geometric data are then coupled with a shading program at runtime to draw the asset.In this paper we describe a system in which pre-processing is done in a compilation process in which the geometric data are processed with knowledge of their shading programs. The data are converted into structures targeted directly to the hardware, and a code stream is assembled that describes the manipulations required to render these data structures. Our compiler is structured like a traditional code compiler, with a front end that reads the geometric data and attributes (hereafter referred to as an
art asset
) output from a 3D modeling package and shaders in a platform independent form and performs platform-independent optimizations, and a back end that performs platform-specific optimizations and generates platform-targeted data structures and code streams.Our compiler back-end has been targeted to four platforms, three of which are radically different from one another. On all platforms the rendering performance of our compiled assets, used in real situations, is well above that of hand-coded assets.
"Pardon me, but your baby is ugly…"
Authors: Marine Larry
Published: October 2002

How many times have we been asked to evaluate a client's Web site or software application for usability? All the design guidelines and standards we have at hand, all the usability tests we conduct, do not ensure that the client will accept our verdict or our recommendations. Larry Marine describes four rules that he has developed to improve the user-centered design methodology and tells us how he uses them to increase the objectivity of his evaluations and make the bad news more easily accepted by the client.--- Elizabeth Buie
Compiling language definitions
Authors: van den Brand Mark G. J. , Heering J. , Klint P. , Olivier P. A.
Published: October 2002

The ASF+SDF Meta-Environment is an interactive language development environment whose main application areas are definition and implementation of domain-specific languages, generation of program analysis and transformation tools, and production of software renovation tools. It uses conditional rewrite rules to define the dynamic semantics and other tool-oriented aspects of languages, so the effectiveness of the generated tools is critically dependent on the quality of the rewrite rule implementation. The ASF+SDF rewrite rule compiler generates C code, thus taking advantage of C's portability and the sophisticated optimization capabilities of current C compilers as well as avoiding potential abstract machine interface bottlenecks. It can handle large (10,000+ rule) language definitions and uses an efficient run-time storage scheme capable of handling large (1,000,000+ node) terms. Term storage uses maximal subterm sharing (hash-consing), which turns out to be more effective in the case of ASF+SDF than in Lisp or SML. Extensive benchmarking has shown the time and space performance of the generated code to be as good as or better than that of the best current rewrite rule and functional language compilers.
Tight bounds on cache use for stencil operations on rectangular grids
Authors: Frumkin Michael A. , Van der Wijngaart Rob F.
Published: October 2002

We derive tight bounds on cache misses for evaluation of explicit stencil operators on rectangular grids. Our lower bound is based on the isoperimetric property of the discrete crosspolytope. Our upper bound is based on a good surface-to-volume ratio of a parallelepiped spanned by a reduced basis of the interference lattice of a grid. Measurements show that our algorithm typically reduces the number of cache misses by a factor of three, relative to a compiler optimized code. We show that stencil calculations on grids whose interference lattices have a short vector feature abnormally high numbers of cache misses. We call such grids unfavorable and suggest to avoid these in computations by appropriate padding. By direct measurements on a MIPS R10000 processor we show a good correlation between abnormally high numbers of cache misses and unfavorable three-dimensional grids.
Whatever became of integrity?
Authors: Ross Paul F.
Published: October 2002

What responsibilities do those in the computing profession have for the moral integrity of what they do?
An intelligent approach to handling imperfect information in concept-based natural language queries
Authors: Owei Vesper
Published: October 2002

Missing information, imprecision, inconsistency, vagueness, uncertainty, and ignorance abound in information systems. Such imperfection is a fact of life in database systems. Although these problems are widely studied in relational database systems, this is not the case in conceptual query systems. And yet, concept-based query languages have been proposed and some are already commercial products. It is therefore imperative to study these problems in concept-based query languages, with a view to prescribing formal approaches to dealing with the problems. In this article, we have done just that for a concept-based natural language query system that we developed. A methodology for handling and resolving each type of imperfection is developed. The proposed approaches are automated as much as possible, with the user mainly serving an assistive function.
It's a Wi-Fi world
Authors: Howard David
Published: October 2002

Wireless broadband may finally be ready for prime time
Computer security
Authors: Mercuri Rebecca T.
Published: October 2002

The challenge of applying protection to systems, software, and networks with intrinsic vulnerabilities is a lofty, but ultimately realizable, one.
Rapid Application Development
Authors: Howard Alan
Published: October 2002

Success in any type of work relies as much on one's attitude toward it as on the skills and techniques applied.
Current and future applications of mobile and wireless networks
Authors: Malladi Rajeswari , Agrawal Dharma P.
Published: October 2002

Wireless and mobile networks are being used in diverse areas such as travel, education, stock trading, military, package delivery, disaster recovery, and medical emergency care.
Local atomicity properties: modular concurrency control for abstract data types
Authors: Weihl W. E.
Published: October 2002

Atomic actions (or transactions) are useful for coping with concurrency and failures. One way of ensuring atomicity of actions is to implement applications in terms ofatomic data types: abstract data types whose objects ensure serializability and recoverability of actions using them. Many atomic types can be implemented to provide high levels of concurrency by taking advantage of algebraic properties of the type's operations, for example, that certain operations commute. In this paper we analyze the level of concurrency permitted by an atomic type. We introduce several local constraints on individual objects that suffice to ensure global atomicity of actions; we call these constraintslocal atomicity properties. We present three local atomicity properties, each of which isoptimal: no strictly weaker local constraint on objects suffices to ensure global atomicity for actions. Thus, the local atomicity properties define precise limits on the amount of concurrency that can be permitted by an atomic type.
Production trees: a compact representation of parsed programs
Authors: Waddle Vance E.
Published: October 2002

Abstract syntax trees were devised as a compact alternative to parse trees, because parse trees are known to require excessive amounts of storage to represent parsed programs. However, the savings that abstract syntax trees actually achieve have never been precisely described because the necessary analysis has been missing. Without it, one can only measure particular cases that may not adequately represent all the possible behaviors.

We introduce a data structure, production trees, that are more compact than either abstract syntax trees or parse trees. Further, we develop the necessary analysis to characterize the storage requirements of parse trees, abstract syntax trees, and production trees and relate the size of all three to the size of the program's text. The analysis yields the parameters needed to characterize these storage behaviors over their entire range. We flesh out the analysis by measuring these parameters for a sample of “C” programs. For these programs, production trees were from 1/15 to 1/23 the size of the corresponding parse tree, l/2.7 the size of a (minimal) abstract syntax tree, and averaged only 2.83 times the size of the program text.
Bacterial Toxins That Modify The Actin Cytoskeleton
Authors: Barbieri Joseph T. , Riese Matthew J. , Aktories Klaus
Published: October 2002

▪ Abstract  Bacterial pathogens utilize several strategies to modulate the organization of the actin cytoskeleton. Some bacterial toxins catalyze the covalent modification of actin or the Rho GTPases, which are involved in the control of the actin cytoskeleton. Other bacteria produce toxins that act as guanine nucleotide exchange factors or GTPase-activating proteins to modulate the nucleotide state of the Rho GTPases. This latter group of toxins provides a temporal modulation of the actin cytoskeleton. A third group of bacterial toxins act as adenylate cyclases, which directly elevate intracellular cAMP to supra-physiological levels. Each class of toxins gives the bacterial pathogen a selective advantage in modulating host cell resistance to infection.
Adenovirus-Mediated Extracellular Superoxide Dismutase Gene Therapy Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta
Authors: Laukkanen Mikko O. , Kivelä Antti , Rissanen Tuomas , Rutanen Juha , Karkkainen Minna K. , Leppanen Olli , Bräsen Jan Hinrich , Yla-Herttuala Seppo
Published: October 2002

Background—Restenosis is a frequent problem after invasive treatment of atherosclerotic vessels and is associated with intimal hyperplasia, which is primarily a result of proliferation and migration of smooth muscle cells, leading to the formation of neointima. Because there is no effective conventional medication for restenosis, gene therapy is a potential new treatment to prevent neointima formation.

Methods and Results—In the present study, we analyzed the effects of adenovirus-mediated extracellular superoxide dismutase (EC-SOD) gene transfer (3×109pfu/kg AdEC-SOD versus AdLacZ control virus) on neointima formation in balloon-denuded rabbit aortas. Local catheter-mediated gene transfer to the arterial wall reduced restenosis (P<0.001) and decreased the number of macrophages in the transduced segment (P<0.001) 2 weeks and 4 weeks after the gene transfer compared with AdLacZ controls. Transgene expression was detected in the arterial wall by RT-PCR 2 weeks after the procedure, and the production of superoxide anion was reduced after the gene transfer. Recovery of the endothelial layer was enhanced in EC-SOD-transduced rabbits compared with LacZ controls (P<0.001) 2 weeks after the gene transfer. The therapeutic effect was found to be extended, affecting the gene transfer site and flanking aortic segments from the renal arteries to the bifurcation. However, systemic AdEC-SOD gene transfer to liver did not have any effects on restenosis.

Conclusions—The results suggest that EC-SOD gene transfer reduces restenosis and may be useful for the prevention of intimal hyperplasia after vascular manipulations.
Constitutive expression of SOCS3 confers resistance to IFN-α in chronic myelogenous leukemia cells
Authors: Sakai Ikuya , Takeuchi Kazuto , Yamauchi Hayato , Narumi Hirosi , Fujita Shigeru
Published: September 2002

Because suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that aberrant SOCS expression confers resistance against cytokine therapy. This study reports on the constitutive expression of SOCS3 in most chronic myelogenous leukemia (CML) cell lines, which are resistant to treatment with interferon α (IFN-α). In contrast, the KT-1/A3 cell line, in which constitutive expression of SOCS3 is barely detectable, is sensitive to IFN-α treatment. Forced expression of SOCS3 in the KT-1/A3 cell line confers resistance to IFN-α treatment. Furthermore, most of the blast cells from patients in CML blast crisis, which are usually resistant to IFN-α therapy, showed constitutive expression of SOCS3. These findings indicate that constitutive SOCS3 expression affects the IFN-α sensitivity of CML cell lines and blast cells from patients with CML blast crisis.
The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production
Authors: Howie Duncan , Okamoto Susumo , Rietdijk Svend , Clarke Kareem , Wang Ninghai , Gullo Charles , Bruggeman Joost P. , Manning Stephen , Coyle Anthony J. , Greenfield Edward , Kuchroo Vijay , Terhorst Cox
Published: September 2002

CD150 (signaling lymphocyte activation molecule [SLAM]) is a self-ligand cell surface glycoprotein expressed on T cells, B cells, macrophages, and dendritic cells. To further explore the role of CD150 signaling in costimulation and TH1 priming we have generated a panel of rat antimouse CD150 monoclonal antibodies. CD150 cell surface expression is up-regulated with rapid kinetics in activated T cells and lipopolysaccharide/interferon γ (IFN-γ)–activated macrophages. Anti-CD150 triggering induces strong costimulation of T cells triggered through CD3. DNA synthesis of murine T cells induced by anti-CD150 is not dependent on SLAM-associated protein (SAP, SH2D1A), because anti-CD150 induces similar levels of DNA synthesis in SAP−/− T cells. Antibodies to CD150 also enhance IFN-γ production both in wild-type and SAP−/− T cells during primary stimulation. The level of IFN-γ production is higher in SAP−/− T cells than in wild-type T cells. Anti-CD150 antibodies also synergize with interleukin 12 (IL-12) treatment in up-regulation of IL-12 receptor β2 mRNA during TH1 priming, and inhibit primary TH2 polarization in an IFN-γ–dependent fashion. Cross-linking CD150 on CD4 T cells induces rapid serine phosphorylation of Akt/PKB. We speculate that this is an important pathway contributing to CD150-mediated T-cell proliferation.
Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis
Authors: Mecklenburgh Katy I. , Walmsley Sarah R. , Cowburn Andrew S. , Wiesener Michael , Reed Benjamin J. , Upton Paul D. , Deighton John , Greening Andrew P. , Chilvers Edwin R.
Published: September 2002

Neutrophil apoptosis represents a major mechanism involved in the resolution of acute inflammation. In contrast to the effect of hypoxia observed in many other cell types, oxygen deprivation, as we have shown, causes a profound but reversible delay in the rate of constitutive apoptosis in human neutrophils when aged in vitro. This effect was mimicked by exposing cells to 2 structurally unrelated iron-chelating agents, desferrioxamine (DFO) and hydroxypyridines (CP-94), and it appeared specific for hypoxia in that no modulation of apoptosis was observed with mitochondrial electron transport inhibitors, glucose deprivation, or heat shock. The involvement of chelatable iron in the oxygen-sensing mechanism was confirmed by the abolition of the DFO and CP-94 survival effect by Fe2+ ions. Although hypoxia inducible factor-1α (HIF-1α) mRNA was identified in freshly isolated neutrophils, HIF-1α protein was only detected in neutrophils incubated under hypoxic conditions or in the presence of DFO. Moreover, studies with cyclohexamide demonstrated that the survival effect of hypoxia was fully dependent on continuing protein synthesis. These results indicate that the neutrophil has a ferroprotein oxygen-sensing mechanism identical to that for erythropoietin regulation and results in HIF-1α up-regulation and profound but reversible inhibition of neutrophil apoptosis. This finding may have important implications for the resolution of granulocytic inflammation at sites of low-oxygen tension.
Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors
Authors: Giraudier Stéphane , Chagraoui Hédia , Komura Emiko , Barnache Stéphane , Blanchet Benoit , LeCouedic Jean Pierre , Smith David F. , Larbret Frédéric , Taksin Anne-Laure , Moreau-Gachelin Françoise , Casadevall Nicole , Tulliez Michel , Hulin Anne , Debili Najet , Vainchenker William
Published: September 2002

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34+ cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34+ cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program.
Rehydration of high-density sickle erythrocytes in vitro
Authors: Holtzclaw J. David , Jiang Maorong , Yasin Zahida , Joiner Clinton H. , Franco Robert S.
Published: September 2002

Recent studies have identified older, low-density sickle red blood cells (SSRBCs) that were resistant to dehydration by valinomycin, a K+ ionophore. These cells, thought to derive from dense SSRBCs that have rehydrated, may represent a terminal cellular phase. To study rehydration, we subjected dense SSRBCs (ρ > 1.107 g/cc) to either oxygenated incubation or rapid oxygenated/deoxygenated (oxy/deoxy) cycling (70 seconds per cycle). Light cells (ρ < 1.087 g/cc) were generated during both oxy incubation (2.9% ± 2.1%; n = 42) and oxy/deoxy cycling (5.3% ± 2.4%; n = 42). The rehydrated cells were K+-depleted (K+ = 20 ± 14 mmol/kg hemoglobin [Hb]) and Na+-loaded (Na+ = 394 ± 106 mmol/kg Hb), and had high levels of external phosphatidylserine. In the presence of external calcium, the generation of rehydrated SSRBCs was inhibited during oxy/deoxy cycling, but the percentage with external phosphatidylserine increased. The calcium-mediated inhibition of rehydration was reversed by charybdotoxin, implying that rehydration was delayed in some cells by the Ca++-activated K+ channel. Preincubation of dense SSRBCs with DIDS (4,4′-di-isothiocyanato-2,2′-disulfostilbene) inhibited the generation of light cells during fast oxy/deoxy cycling, but not during oxy incubation. These results suggest that the sickling-induced pathway, previously implicated in SSRBC dehydration, may be involved in the deoxy-dependent component of rehydration for dense, K+-depleted cells. Light-cell generation was inhibited by 1 mM bumetanide during both oxy incubation and oxy/deoxy cycling, providing evidence that a bumetanide-sensitive, deoxy-independent pathway, previously described in circulating light SSRBCs, also contributes to the rehydration of high-density SSRBCs.
Engagement of the inhibitory receptor CD158a interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction
Authors: Guerra Nadia , Michel Frédérique , Gati Asma , Gaudin Catherine , Mishal Zohar , Escudier Bernard , Acuto Oreste , Chouaib Salem , Caignard Anne
Published: September 2002

Renal cell carcinoma (RCC) infiltrating lymphocytes (TILs) express killer cell immunoglobulinlike receptors (KIRs) that inhibit the antitumor CD8+ T-cell lysis. In the present study, to better examine the functional consequences of KIR engagement on cytotoxic T lymphocyte (CTL)/tumor interaction, we have investigated the influence of KIR CD158a on early steps of T-cell activation. We show that coengagement of T-cell receptor (TCR) and CD158a by tumor cells inhibited tyrosine phosphorylation of early signaling proteins ZAP-70 and LAT, lipid raft coalescence, and TCR/CD3 accumulation at the CTL/tumor cell interface. In addition, the guanine exchange factor Vav was not phosphorylated, and no actin cytoskeleton rearrangement was observed. Our data indicate a role of KIR CD158a in the dynamic events induced by TCR triggering, preventing CTL membrane reorganization, and subsequent completion of CTL activation program. Accordingly, the expression of CD158 by TILs may favor tumor cell escape to the immune response.
Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome
Authors: Juszczynski Przemyslaw , Kalinka Ewa , Bienvenu Jacques , Woszczek Grzegorz , Borowiec Maciej , Robak Tadeusz , Kowalski Marek , Lech-Maranda Ewa , Baseggio Lucile , Coiffier Bertrand , Salles Gilles , Warzocha Krzysztof
Published: September 2002

Tumor necrosis factor (TNF) production and non-Hodgkin lymphoma (NHL) outcome was found to be related to the TNF−308polymorphism. To explore whether this could be linked to neighboring polymorphisms, we genotyped the TNF−376,−308,−238,−163, lymphotoxin alpha (LTα)+252, and HLA DRB1 alleles in 204 patients with NHL and 120 controls. TNF−308A was the only allele associated with higher TNF and its p55 and p75 receptors' levels (P = .009, P = .03, andP = .007) and lower complete remission rates (P = .006). Freedom from progression (FFP) and overall survival (OS) were shorter in patients with TNF−308A(P = .009 and P = .02), null HLA DRB1*02 allele (P = .007 and P = .14), or both genetic markers (P = .004 and P = .005). Multivariate analysis incorporating International Prognostic Index (IPI) identified TNF−308A (P < .0001, relative risk [RR] = 1.63; P < .0001, RR = 1.51) and null HLA DRB1*02 alleles (P = .015, RR = 1.18;P < .0001, RR = 1.25) as independent factors for FFP and OS. These results indicate the existence of at least 2 inherited factors involved in NHL outcome.
Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis
Authors: Testa Ugo , Riccioni Roberta , Militi Stefania , Coccia Eliana , Stellacci Emilia , Samoggia Paola , Latagliata Roberto , Mariani Gualtiero , Rossini Annalisa , Battistini Angela , Lo-Coco Francesco , Peschle Cesare
Published: September 2002

We have investigated the expression of interleukin-3 receptor α (IL-3Rα) chain in primary blasts from 79 patients with acute myeloid leukemia (AML), 25 patients with B-acute lymphoid leukemia (B-ALL), and 7 patients with T-acute lymphoid leukemia (T-ALL) to evaluate a linkage between the expression of this receptor chain, blast proliferative status, and disease prognosis. Although IL-3Rα chain was scarcely expressed in most patients with T-ALL, it was overexpressed in 40% and 45% of patients with B-ALL and AML, respectively, compared with the levels observed in normal CD34+ progenitors. The biological and clinical significance of this overexpression pattern was investigated in AML. At the biological level, elevated IL-3Rα expression was associated with peculiar properties of leukemic blasts, specifically in 3 areas. First, in all patients the blasts expressing elevated IL-3Rα levels exhibited higher cycling activity and increased resistance to apoptosis triggered by growth factor deprivation. Second, spontaneous signal transducer and activator of transcription 5 (Stat5) phosphorylation was observed in 13% of AML patients, all pertaining to the group of patients exhibiting high IL-3Rα expression. Third, following IL-3 treatment, Stat5 was activated at higher levels in blasts with elevated IL-3Rα expression. At the clinical level, a significant correlation was observed between the level of IL-3Rα expression and the number of leukemic blasts at diagnosis, and patients exhibiting elevated IL-3Rα levels had a lower complete remission rate and survival duration than those showing normal IL-3Rα levels. These findings suggest that in AML, deregulated expression of IL-3Rα may contribute to the proliferative advantage of the leukemic blasts and, hence, to a poor prognosis.
Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency
Authors: Rezende Suely M. , Lane David A. , Mille-Baker Blandine , Samama Michel M. , Conard Jacqueline , Simmonds Rachel E.
Published: September 2002

We have identified 2 PROS1 missense mutations in the exon that encodes the vitamin K–dependent Gla domain of protein S (Gly11Asp and Thr37Met) in kindred with phenotypic protein S deficiency and thrombosis. In studies using recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor Va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (P < .001) and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (P < .0001) and decreased affinity for an antibody specific for the Ca2+-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only a modest 1.5-fold (P < .001), reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterization of natural protein S Gla-domain variants highlights the importance of the high affinity protein S–phospholipid interaction for its anticoagulant role.
Comparison of T-cell–depleted and non–T-cell–depleted unrelated donor transplantation for hematologic diseases: clinical outcomes, quality of life, and costs
Authors: Lee Stephanie J. , Zahrieh David , Alyea Edwin P. , Weller Edie , Ho Vincent T. , Antin Joseph H. , Soiffer Robert J.
Published: September 2002

T-cell depletion (TCD) and immunosuppressive medications (ISTs) are 2 methods used for graft-versus-host disease (GVHD) prophylaxis in unrelated donor (URD) transplantation. However, comparisons of the clinical outcomes including quality of life and direct medical costs associated with each type of procedure have not been reported. We reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99 at the Dana-Farber Cancer Institute, Boston, MA. With a median follow-up of 1.5 years for survivors, no differences were seen in relapse, acute GVHD, and overall survival between TCD and IST patients. Multivariable Cox modeling showed that age of 50 years or less (P = .002) and low-risk disease (P = .001) predicted survival, but method of GVHD prophylaxis (P = .6) and degree of human leukocyte antigen (HLA) matching (P = .8) did not. A subset of patients (53%) completed quality of life surveys prior to and at 6 and 12 months after transplantation; participation in the quality of life study was not associated with clinical characteristics and outcomes. No differences were seen in quality of life scores prior to transplantation, and changes over time were similar between groups. Costs ($113 000 vs $155 000, P < .0001) and total hospital days (34 vs 46, P = .0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully understand the overall impact of each intervention.
Negative prognostic value of glutathione S-transferase(GSTM1 and GSTT1) deletions in adult acute myeloid leukemia
Authors: Voso Maria Teresa , D'Alo' Francesco , Putzulu Rossana , Mele Luca , Scardocci Alessandra , Chiusolo Patrizia , Latagliata Roberto , Lo-Coco Francesco , Rutella Sergio , Pagano Livio , Hohaus Stefan , Leone Giuseppe
Published: September 2002

Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of several environmental mutagens, carcinogens, and anticancer drugs. GST polymorphisms resulting in decreased enzymatic activity have been associated with several types of solid tumors. We determined the prognostic significance of the deletion of 2 GST subfamilies genes, M1 and T1, in patients with acute myeloid leukemia (AML). Using polymerase chain reactions, we analyzed theGSTM1 and GSTT1 genotype in 106 patients with AML (median age, 60.5 years; range, 19-76 years). The relevance ofGSTM1 and GSTT1 homozygous deletions was studied with respect to patient characteristics, response to therapy, and survival. Homozygous deletions resulting in null genotypes at theGSTM1 and GSTT1 loci were detected in 45 (42%) and 30 (28%) patients, respectively. The double-null genotype was present in 19 patients (18%). GST deletions predicted poor response to chemotherapy (P = .04) and shorter survival (P = .04). The presence of at least one GST deletion proved to be an independent prognostic risk factor for response to induction treatment and overall survival in a multivariate analysis including age and karyotype (P = .02). GST genotyping was of particular prognostic value in the cytogenetically defined intermediate-risk group (P = .003). In conclusion, individuals with GSTM1 or GSTT1 deletions (or deletions of both) may have an enhanced resistance to chemotherapy and a shorter survival.
Activation of the Jak3 pathway is associated with granulocytic differentiation of myeloid precursor cells
Authors: Rane Sushil G. , Mangan James K. , Amanullah Arshad , Wong Brian C. , Vora Renu K. , Liebermann Dan A. , Hoffman Barbara , Graña Xavier , Reddy E. Premkumar
Published: September 2002

Jak3, a member of the Janus kinase family of cytoplasmic tyrosine kinases, is expressed at low levels in immature hematopoietic cells and its expression is dramatically up-regulated during the terminal differentiation of these cells. To better understand the role of Jak3 in myeloid cell development, we have investigated the role of Jak3 in myeloid cell differentiation using the 32Dcl3 cell system. Our studies show that Jak3 is a primary response gene for granulocyte colony-stimulating factor (G-CSF) and the accumulation of tyrosine phosphorylated Jak3 correlated with cell growth inhibition and terminal granulocytic differentiation in response to G-CSF. Ectopic overexpression of Jak3 in 32Dcl3 cells resulted in an acceleration of the G-CSF–induced differentiation program that was preceded by G1 cell cycle arrest, which was associated with the up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 and down-regulation of Cdk2, Cdk4, Cdk6, and Cyclin E. In addition, ectopic overexpression of Jak3 appears to result in the inactivation of PKB/Akt and Stat3-mediated proliferative pathways in the presence of G-CSF. Similarly, overexpression of Jak3 in primary bone marrow cells resulted in an acceleration of granulocytic differentiation in the presence of granulocyte-macrophage colony-stimulating factor, which was associated with their growth arrest in the G1 phase of the cell cycle. Taken together, these results indicate that Jak3-mediated signals play an important role in myeloid cell differentiation.
Latent cytomegalovirus down-regulates major histocompatibility complex class II expression on myeloid progenitors
Authors: Slobedman Barry , Mocarski Edward S. , Arvin Ann M. , Mellins Elizabeth D. , Abendroth Allison
Published: September 2002

Following primary infection, human cytomegalovirus (CMV) establishes a lifelong latent infection in bone marrow–derived myeloid lineage cells. Although downmodulation of major histocompatibility complex (MHC) class I and class II protein levels occurs during active viral replication, little is known about the modulation of these proteins during latent infection. When analyzed by flow cytometry, latently infected adherent cells collected from granulocyte macrophage progenitor (GM-P) cultures exhibited a striking reduction in MHC class II antigen present on the cell surface starting very early after exposure to virus that continued for more than 2 weeks. In comparison, cell surface levels of the monocyte cell surface marker CD14 remained unaltered in these cells. A recombinant virus (RV798) lacking the virus genes US2-US11 retained the ability to downmodulate MHC class II levels during latent infection. Immunoblot and immunofluorescent antibody staining analyses showed that the reduction in MHC class II surface levels during latency was associated with a block in protein trafficking. HLA-DR was retained within cytoplasmic vesicles that also contained HLA-DM. Thus, downmodulation remained independent of all previously characterized MHC class I and class II immunomodulatory viral gene products and involved a mechanism not previously ascribed to any viral function. These data show that latent infection is accompanied by reduced cell surface expression of MHC class II proteins, a strategy that would afford the virus escape from immunosurveillance and increase the chances for lifelong latent infection.
Increased bone marrow allograft rejection by depletion of NK cells expressing inhibitory Ly49 NK receptors for donor class I antigens
Authors: Raziuddin Arati , Longo Dan L. , Bennett Michael , Winkler-Pickett Robin , Ortaldo John R. , Murphy William J.
Published: September 2002

Natural killer (NK) cells are the major effectors of acute rejection of incompatible bone marrow cell (BMC) grafts in lethally irradiated mice. The immunogenetics of BMC rejection are largely controlled by the coexpression (or not) of inhibitory and stimulatory Ly49 receptors whose ligands are class I major histocompatibility complex (MHC) molecules. The majority of the BMC rejection studies involved low numbers of BMCs that were resisted by host NK cells. In the present study, larger numbers of BMCs were given in which rejection was not detected and the role of different Ly49 NK subsets not presumably involved in the rejection of a particular BMC haplotype was examined. Surprisingly, the data show that the removal of NK cell subsets expressing Ly49 inhibitory receptors for donor class I antigens, which would be predicted to have no effect on the BMC rejection capability, resulted in the marked rejection of BMCs where no resistance was normally seen. These results extend the “missing self” hypothesis to suggest that NK Ly49 inhibitory receptors can both inhibit activation and killing by those cells, but also can in some way influence the function of NK cells that do not express that inhibitory receptor in a cell-cell interaction. This suggests that caution must be exercised before removal of host NK cell subset is applied clinically because enhanced BMC rejection may result. Altering the balance of Ly49 NK subsets may also affect other in vivo activities of these cells.
Environmental changes during isolation processes from the Litorina Sea as reflected by diatoms and geochemical parameters -a case study
Authors: Westman Per , Hedenström Anna
Published: September 2002

The aim with the present case study was to detect environmental changes during the isolation of a lake from the Baltic Sea. Elemental and stable-isotope ratios of carbon and nitrogen are presented as well as results of a diatom analysis of a sedimentary sequence from Lake Skären in southeastern Sweden. The dated part of the analysed sequence covers the period c. 8200 to 7000 cal. years BP, i.e., the late Ancylus Lake to early Litorina Sea stages. It is concluded that subtle environmental changes due to ‘ uctuations in input of organic material from different sources cannot be detected by diatom analysis alone, but that chemostratigraphy is an important complement to diatom stratigraphy when interpreting the isolation process. We also conclude that, even though δ13C is highly variable in Baltic Sea sediment, it is most useful in isolation studies for recording the contribution of organic carbon derived from benthic macro-algae and/or terrestrial sources, as a proxy for shore displacement. It is especially valuable in combination with the C/N ratio, which seems to be the most unambiguous parameter. The δ15N data showed that cyanobacterial blooms in the coastal zone of the early Litorina Sea were probably less pronounced than in the offshore areas of the Baltic Sea. The abrupt increase of Chaetoceros spp. resting spores slightly prior to isolation is interpreted as caused by a eutrophication process during the isolation: it is probably also due to nitrogen deficiency due to denitrification in the coastal areas.
Neolithic to Copper Age woodland impacts in northeast Hungary? Evidence from the pollen and sediment chemistry records
Authors: Gardner A. R.
Published: September 2002

A 4.5 m sedimentary sequence collected from Sirok Nýrjes Tó in northeast Hungary reveals a record of environmental change from 10000 BP to the present day. Palaeoenvironmental analyses (pollen, charcoal, geochemistry and physical properties) of the sequence reveal an environment where parkland com posed of coniferous and broadleaved taxa existing at the start of the Holocene developed rapidly into deciduous broadleaved forest. From c. 8200 cal. BP, Corylus expanded rapidly and dominated the pollen assemblage until a series of fluctuations involving Corylus and Carpinus betulus which resulted in changes to the forest compo sition. These changes occurred over timescales of 72–288 years and are attributed to Neolithic and Copper Age forest use, perhaps under a woodland management regime such as coppicing or pollarding. Sedimentolog ical and geochemical records for this period are stable, suggesting that soil erosion was not occurring. Natural forest processes resumed following Copper Age settlement shifts but were subject to further, more extreme impacts during the Hungarian migrations and conquests of the 1st millennium ad. Landscape clearance is not evident until c. 2000 cal. BP, but was of insufficient intensity to initiate soil erosion.
Annual and decadal climate forcing of historical fire regimes in the interior Pacific Northwest, USA
Authors: Heyerdahl Emily K. , Brubaker Linda B. , Agee James K.
Published: September 2002

Anticipating the consequences of climatic change for fire requires understanding of the causes of variation in historical fire regimes. We assessed the influence of annual and decadal variation in climate on fire regimes of ponderosa pine-dominated forests in eastern Oregon and Washington using existing, annually dated tree-ring reconstructions (1687–1994). In four watersheds, we compared the extent of low-severity fires (total area burned each year) to precipitation and the Southern Oscillation Index, a measure of variation in El Niño-Southern Oscillation (ENSO), which affects weather in this region. At the annual scale, large fires burned during dry years and El Niño years (low SOI) in all watersheds while small fires burned regardless of variation in these climate parameters. Large fires also burned during relatively wet years and La Niña years (high SOI) in one watershed, indicating that local factors can override regional climate controls in some locations. Climate from previous years did not influence current year's fire extent. The influence of ENSO on fire regimes in this region has not previously been demonstrated at these multicentury, regional scales. At the decadal scale, fire extent varied with precipitation, perhaps in response to variation in such climate features as the Pacific Decadal Oscillation. Several decades of low fire extent in the watersheds during the early 1800s was synchronous with a lack of fire at other sites in North and South America, probably in response to a change in the global climate that included a lessening in the frequency and/or intensity of ENSO events.