bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Uncertainty and Variability in Residential Radon Cancer Risks
Authors: KREWSKI D. , RAI S. N. , ZIELINSKI J. M. , HOPKE P. K.
Published: February 2006

Abstract: Radon, a naturally occurring gas found at some level in most homes, is an established risk factor for human lung cancer. The U.S. National Research Council has recently completed a comprehensive evaluation of the health risks of residential exposure to radon and developed models for projecting radon lung cancer risks to the general population. This analysis suggests that radon may play a role in the etiology of 10–15% of all lung cancer cases in the United States, although these estimates are subject to considerable uncertainty. In this article, we present a detailed analysis of uncertainty and variability in estimates of lung cancer risk due to residential exposure to radon. We use a general framework for the analysis of uncertainty and variability that we developed previously. Specifically, we focus on estimates of the age‐specific excess relative risk (ERR) and lifetime relative risk (LRR), both of which vary substantially among individuals. We also consider estimates of the population attributable risk (PAR), which reflects the proportion of the lung cancer burden attributable to radon. Variability in the ERR and LRR is largely determined by variability in residential exposure levels and in the dosimetric K‐factor used to extrapolate from occupational to environmental settings. Uncertainty in the ERR and LRR is due to uncertainty in the model parameters, notably those reflecting the carcinogenic potency of radon and the modifying effect of attained age. Uncertainty in the PAR is determined by uncertainty about the values of the parameters in the risk models used to estimate the PAR. Uncertainty in radon levels in homes and the dosimetric K‐factor contribute comparatively little to uncertainty in the PAR. These results suggest that reduction in uncertainty about the PAR for radon induced lung cancer can only be achieved if more reliable risk projection models can be developed.
Risk Assessment‐the Mother of All Uncertainties: Disciplinary Perspectives on Uncertainty in Risk Assessment
Authors: BAILAR JOHN C. , BAILER A. JOHN
Published: February 2006

Abstract: Uncertainty in the detection and evaluation of chemical hazards to health leads to challenges when conducting risk assessments. Some of the uncertainty has to do with data, some with incomplete understanding of processes, and some with the most fundamental ways of viewing the questions. True variability‐across space, in time, or among individuals‐complicates the search for understanding many important aspects of risk. A few statistical and toxicologic tools are available to assess uncertainty. Three methods of classifying uncertainty are briefly discussed. In addition, our disciplinary background may influence how we view and discuss variability and uncertainty. We rarely know as much as we think we do (and not just in risk assessment). Great uncertainty is likely to remain an important part of risk assessment for some decades to come.
Distributions of Individual Susceptibility among Humans for Toxic Effects: How Much Protection Does the Traditional Tenfold Factor Provide for What Fraction of Which Kinds of Chemicals and Effects?
Authors: HATTIS DALE , BANATI PRERNA , GOBLE ROBERT
Published: February 2006

Abstract: A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half‐life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity‐change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log‐normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.
Analysis of PBPK Models for Risk Characterization
Authors: BOIS FRÉDÉRIC YVES
Published: February 2006

Abstract: Adoption of a Bayesian framework for risk characterization permits the seamless integration of different kinds of information available in order to choose and parameterize risk models. It also becomes easy to disentangle uncertainty from variability, through hierarchical statistical modeling. Appropriate numerical techniques can be found, for example, in the recently developed arsenal of Markov chain, Monte Carlo simulations. The developments in this area can actually be viewed as extensions of the traditional or standard Monte Carlo methods for uncertainty analysis. Following a brief review of the techniques, examples of Bayesian analyses of physiologically‐based pharmacokinetic models are presented for tetrachloroethylene and dichloromethane. The discussion touches on some open problems and perspectives for the proposed methods.
Epidemiology of Socioeconomic Status and Health: Are Determinants Within Countries the Same as Between Countries?
Authors: MARMOT MICHAEL
Published: February 2006

Abstract:Within societies, health and ill‐health follow a social gradient: lower socioeconomic position, worse health. The slope of the gradient has varied over time. It is likely that social and economic circumstances play a role in this changing slope. Within Europe, differences in health between East and West have also varied in magnitude. The advantage in the West increased through the 1970s and 1980s. Although similar in their health trends up to 1989, the countries of central and eastern Europe have diverged quite sharply subsequently. It is again likely that changing social and economic fortunes account for these trends. There is evidence to support the role of psychosocial factors in relating to socioeconomic differences within and between countries.
Health, Hierarchy, and Social Anxiety
Authors: WILKINSON RICHARD G.
Published: February 2006

Abstract:This paper suggests that the main reasons why populations with narrower income differences tend to have lower mortality rates are to be found in the psychosocial impact of low social status. There is now substantial evidence showing that where income differences are greater, violence tends to be more common, people are less likely to trust each other, and social relations are less cohesive. The growing impression that social cohesion is beneficial to health may be less a reflection of its direct effects than of its role as a marker for the underlying psychological pain of low social status. Low social status affects patterns of violence, disrespect, shame, poor social relations, and depression. In its implications for feelings of inferiority and insecurity, it interacts with other powerful health variables such as poor emotional attachment in early childhood and patterns of friendship and social support. Causal pathways are likely to center on the influence that the quality of social relations has on neuroendocrine pathways.
Hierarchies of Life Histories and Associated Health Risks
Authors: SINGER BURTON , RYFF CAROL D.
Published: February 2006

Abstract: Widely documented inverse associations between socioeconomic standing and incident chronic disease and mortality invite explanation in terms of pathways to these outcomes. Empirical identification of pathways, or histories, requires measures that assess cumulative wear and tear on physiological systems following from psychosocial adversity and genetic predispositions. Such an assessment, allostatic load, has been shown to predict later life mortality, incident cardiovascular disease, and decline in physical and cognitive functioning. Using data from the Wisconsin Longitudinal Study (WLS), we seek precursors to allostatic load via ordered categories of cumulative adversity relative to advantage over the life course. We operationalize these histories via unfolding economic circumstances and social relationship experiences (e.g., parent‐child interactions, quality of spousal ties). Findings reveal a strong direct association between the extent of adversity relative to advantage in an ordering of these histories and likelihood of high allostatic load. Importantly, resilient individuals with economic disadvantage, but compensating positive social relationship histories also show low prevalence of high allostatic load.
Social Capital and Community Effects on Population and Individual Health
Authors: KAWACHI ICHIRO
Published: February 2006

Abstract: Social capital refers to those features of social relationships‐such as levels of interpersonal trust and norms of reciprocity and mutual aid‐that facilitate collective action for mutual benefit. Social capital is believed to play an important role in the functioning of community life across a variety of domains, ranging from the prevention of juvenile delinquency and crime, the promotion of successful youth development, and the enhancement of schooling and education to the encouragement of political participation. More recently, researchers have begun to apply the concept to explain variations in health status across geographic localities. In preliminary analyses, the higher the stocks of social capital (as indicated by measures of trust and reciprocity in social surveys), the higher appear to be the health achievement of a given area. Strengthening the social capital within communities may provide an important avenue for reducing socioeconomic disparities in health.
Pathways by Which SES and Ethnicity Influence Cardiovascular Disease Risk Factors
Authors: WINKLEBY MARILYN A. , CUBBIN CATHERINE , AHN DAVID K. , KRAEMER HELENA C.
Published: February 2006

Abstract: Little is known about pathways by which socioeconomic status (SES) translates into individual differences in cardiovascular disease (CVD) risk factors. Because the socioeconomic structure is not the same for all ethnic subgroups, the pathways that lead to the development of CVD risk factors may vary by both SES and ethnicity. We used data from a large national survey to examine the independent associations of two indicators of SES (education and income) and ethnicity with six primary CVD risk factors. We then used data on smoking that reflected a temporal sequence to examine the extent to which SES and ethnicity influenced smoking at three different time points, from smoking onset, to a serious quit attempt, to successful quitting. These analyses provide an understanding of the relationships between SES, ethnicity, and CVD risk factors and suggest that if the timing, focus, and content of intervention programs take pathways into account they will result in more successful outcomes.
Psychosocial Resources and the SES‐Health Relationship
Authors: TAYLOR SHELLEY E. , SEEMAN TERESA E.
Published: February 2006

Abstract:Psychosocial resources, which include optimism, coping style, a sense of mastery or personal control, and social support, influence the relationship between SES and health. To varying degrees, these resources appear to be differentially distributed by social class and related to health outcomes. Such resources may partially mediate the impact of SES on health. For example, environments that undermine personal control may have an impact on chronic arousal and the corresponding development of disease, such as CHD. Psychosocial resources may also moderate the impact of SES on health. For example, a large number of positive social relationships and a few conflictual ones may buffer individuals against the adverse effects of SES‐related stress. These psychosocial resources are moderately intercorrelated, and so a research strategy that explores their coherence as a psychosocial profile that promotes resilience to stress is tenable and merits empirical examination. The erosion of these resources as one moves lower on the SES scale and specific factors that contribute to such erosion are discussed.
Do Negative Emotions Mediate the Association between Socioeconomic Status and Health?
Authors: GALLO LINDA C. , MATTHEWS KAREN A.
Published: February 2006

Abstract:In this chapter, we examine the possibility that negative emotions contribute to the relationship between socioeconomic status (SES) and health. A model of the associations among SES, emotion, and health is presented first. We then review the evidence for this model, showing associations of SES with depression, hopelessness, anxiety, and hostile affect and cognition, and of these negative emotions with disease. Notably, most of the data supporting the model provide only indirect evidence that negative emotions serve as a key contributor to the proposed associations. We, therefore, conclude with recommendations for longitudinal research, especially in children, that will more directly and comprehensively examine negative emotions as possible mediators of the SES and health relationship.
Social Status and Susceptibility to Respiratory Infections
Authors: COHEN SHELDON
Published: February 2006

Abstract: Adults and children of lower socioeconomic status (SES) are at higher risk for a wide range of communicable infectious diseases, especially respiratory infections. Greater risk for infectious illness among people with lower SES is thought to be attributable to increased exposure to infectious agents and decreased host resistance to infection. We summarize three studies that examine the prospective association of several markers of social status (unemployment, perceived and observed social status) with host resistance to upper respiratory infections. Unemployment was associated with increased susceptibility to infection in adult humans. Lower social status in male monkeys was also associated with increased susceptibility, as was lower perceived social status in humans. The association of social status and susceptibility was accounted for primarily by increased risk in the lowest social status groups. However, further increases in social status were associated with further decreases in susceptibility in both monkeys and humans.
Socioeconomic Status and Health: Policy Implications in Research, Public Health, and Medical Care
Authors: LEE PHILLIP R.
Published: February 2006

Abstract: The role of public policy in research, public health, and medical care is discussed as well as the extent to which public policy has been informed by increased knowledge about the relationship between SES and health and to what extent policy has affected SES‐related health disparities. Observations on current healthcare policy and recommendations for the future are offered.
Expression of Novel Surface Antigens on Early Hematopoietic Cellsa
Authors: BÜHRING HANS‐JÖRG , SEIFFERT MARTINA , BOCK THOMAS A. , SCHEDING STEFAN , THIEL ANDREAS , SCHEFFOLD ALEXANDER , KANZ LOTHAR , BRUGGER WOLFRAM
Published: February 2006

Abstract: The purpose of this report is to demonstrate the expression of very recently identified surface antigens on CD34+ and AC133+ bone marrow (BM) cells. Coexpression analysis of AC133 and defined antigens on CD34+ BM cells revealed that the majority of the CD164+, CD135+, CD117+, CD38low, CD33+, and CD71+ cells resides in the AC133+ population. In contrast, most of the CD10+ and CD19+ B cell progenitors and a fraction of the CD71high population are AC133−, indicating that CD34+AC133+ cells are enriched in primitive and myeloid progenitor cells, whereas CD34+AC133− cells mainly consist of B cell and late erythroid progenitors. This corresponds to the highly reduced percentage of CD10+ B cells and the absence of CD71high erythroid progenitors on AC133+ selected BM cells. A portion of 0.2‐0.7% of the AC133+ selected cells do not coexpress CD34. These cells are very small and define a uniform CD71−, CD117−, CD10−, CD38low, CD135+, HLA‐DRhigh, CD45+ population with unknown delineation. Four color analysis on CD34+CD38− BM cells revealed that virtually all of these primitive cells express AC133. Using an improved liposome‐enhanced labeling technique for the staining of weakly expressed antigens, subsets of this population could be identified which express the angiopoietin receptors TIE (67.6%) and TEK (36.8%), the vascular endothelial growth factor receptors FLT1 (7%), FLT4 (3.2%), and KDR (10.4%), or the receptor tyrosine kinases HER‐2 (15.4%) and FLT3 (CD135; 77.6%). Our results suggest that the CD34+CD38− population is heterogeneous with respect to the expression of the analyzed receptor tyrosine kinases.
Lymphohematopoietic Stem Cell Engraftmenta
Authors: QUESENBERRY PETER J. , STEWART F. MARC , ZHONG SUJU , HABIBIAN HOURI , MCAULIFFE CHRISTINA , REILLY JUDY , CARLSON JANE , DOONER MARK , NILSSON SUSIE , PETERS STEFAN , STEIN GARY , STEIN JANET , EMMONS ROB , BENOIT BRIAN , BERTONCELLO IVAN , BECKER PAMELA
Published: February 2006

Abstract: Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation.

The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL‐3, IL‐6, IL‐11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy.
Biology of IL‐8‐Induced Stem Cell Mobilization
Authors: FIBBE WILLEM E. , PRUIJT JOHANNES F.M. , VELDERS GERJO A. , OPDENAKKER GHISLAIN , KOOYK GYVETTE VAN , FIGDOR CARL G. , WILLEMZE ROEL
Published: February 2006

Abstract: The CXC chemokine interleukin‐8 (IL‐8) has profound hematopoietic activities following systemic administration. It induces the rapid mobilization of cells with lymphomyeloid repopulating ability in mice and of hematopoietic progenitor cells in monkeys. In this paper, evidence is presented that stem cell mobilization in mice requires the functional expression on the β2‐integrin leukocyte function‐associated antigen‐1 (LFA‐1). In monkeys, systemic injection of IL‐8 is followed by a significant increase in the circulating levels of the matrix metallo proteinase gelatinase‐B (MMP‐9). Based on these findings, the hypothesis is discussed that mature neutrophils serve as intermediate cells in IL‐8‐induced stem cell mobilization by the release of proteinases.
(R)Evolutionary Considerations in Hematopoietic Development
Authors: COOPER DONNA D. , SPANGRUDE GERALD J.
Published: February 2006

Abstract: Evolutionary aspects of three characteristics of the mammalian hematopoietic system are considered in the context of both established and recent data. First, the lineage relationships among early members of the hematopoietic hierarchy are reconsidered in a tripartite model proposing lineage segregation based on vascular function, innate immunity, and acquired immunity on an evolutionary time scale. Second, the observation of two stem cell populations that differ in cell cycle status is considered as an evolved mechanism to enhance survival of the species in response to exposure to environmental toxins. Finally, the mobilization of hematopoietic stem cells into the peripheral circulation is proposed to be a mechanism for rapid dissemination of myeloid function during acute bacterial infections. These revolutionary hypotheses challenge some conventional concepts of stem cell biology, and provide an evolutionary context for considering mammalian hematopoiesis.
Stem Cell Gene Therapy for the β‐Chain Hemoglobinopathies: Problems and Progressa
Authors: EMERY DAVID W. , STAMATOYANNOPOULOS GEORGE
Published: February 2006

Abstract: Virus vectors hold great promise for the stem cell gene therapy of β‐chain hemoglobinopathies. However, conventional vectors suffer from low gene transfer rates, low expression levels, and inconsistent or short‐lived expression in vivo. In this review we summarize the current status of vector systems for the transduction of hematopoietic stem cells, including the development of novel vector systems and methods for selection of transduced stem cells in vivo. We also summarize efforts to achieve therapeutic expression levels of transferred globin genes with retrovirus vectors, including the manipulation of transcription cassettes, the use of globin gene enhancers, and advances in the use of chromatin insulators for improving the frequency of gene expression following hematopoietic stem cell transduction.
Retroviral‐Fibronectin Interactions in Transduction of Mammalian Cells
Authors: WILLIAMS DAVID A.
Published: February 2006

Abstract: Hematopoiesis occurs in a complex environment in the medullary cavity in close proximity to stromal cells, fibroblasts, endothelial cells and matrix molecules. Hematopoietic cell interactions in this environment appear to involve both integrin and proteoglycan‐mediated cell‐cell and cell‐matrix interactions. Genetic transduction of hematopoietic stem cells via retroviral vectors has been hampered by low efficiency of gene transfer. Recently, hematopoietic stem cell adhesion to the extracellular matrix molecule fibronectin has been shown to increase transduction of these target cells using retrovirus vectors. The mechanism of increased transduction appears to involve colocalization of virus particles and target cells. These data are reviewed in this paper.
Dissecting the Marrow Microenvironment
Authors: TOROK‐STORB BEVERLY , IWATA MINEO , GRAF LYNN , GIANOTTI JOANN , HORTON HEIDI , BYRNE MICHAEL C.
Published: February 2006

Abstract: Cloned human stromal cell lines representing functionally distinct cellular components of the marrow microenvironment were generated to serve as tools for identifying gene products that regulate hematopoiesis. Oligonucleotide arrays, or “gene chips” were used to provide a comprehensive comparison of gene expression among the cell lines. One line, designated HS‐5, was found to secrete large amounts of cytokines, and conditioned media from this line was found to support the ex vivo expansion of both immature and mature progenitors. In contrast, a second line, designated HS‐27a, does not secrete known cytokines but does support cobblestone area formation by CD34+/38lo cells. HS‐27a, but not HS‐5, was also found to express hJagged1, a ligand for Notch1, which may function to influence cell fate decisions of hematopoietic precursors. Both cell lines are currently being used to identify other gene products that regulate hematopoiesis and to generate reagents that will allow more formal evaluation of the putative role of hJagged1 in hematopoietic cell fate decisions.
Hematopoietic Stem/Progenitor Cell Mobilization: A Continuing Quest for Etiologic Mechanisms
Authors: PAPAYANNOPOULOU THALIA
Published: February 2006

Abstract: The physiologic egress of mature hemopoietic cells and of hemopoietic stem/progenitor cells from bone marrow to the circulation are poorly understood processes. Likewise, the mechanism of their enforced emigration or mobilization through the use of several agents has not been unraveled. Although mobilization is suspected to be a multi‐step process, involving equential and/or overlapping changes in adhesion and migratory capacity, a model of molecular hierarchy, like the one governing the extravasation of mature leukocytes to tissues of inflammation, has not been worked out. Understanding the in vivo mechanism of mobilization has been a challenge. Signals emanating from both stromal cells and from hemopeietic cells are likely involved. However, dissecting out their roles, specificity, and interactions has been difficult. Nevertheless insightful information is rapidly emerging, especially with the current availability of many mouse models bearing targeted disruptions of cytoadhesion or signaling molecules.
Absence of CD34 on Some Human SCID‐Repopulating Cells
Authors: DICK JOHN E.
Published: February 2006

Abstract: The availability of in vivo repopulation assays had greatly aided the study of human hematopoietic stem cells. Here, I shall review recent data that has identified a novel class of human repopulating cells that do not express classical stem cell markers including CD34 but still retain the ability to repopulate nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.
Engraftment and Multilineage Expression of Human Bone Marrow CD34− Cells In Vivoa
Authors: ZANJANI ESMAIL D. , ALMEIDA‐PORADA GRAÇA , LIVINGSTON ANNE G. , PORADA CHRISTOPHER D. , OGAWA MAKIO
Published: February 2006

Abstract: The fetal sheep competitive engraftment model of human hematopoietic stem cells (HSC) was used to evaluate the in vivo engraftment potential of human bone marrow CD34− Lin− cells. Transplantation of CD34− Lin− cells into primary hosts resulted in the long‐term (>1 year) engraftment and multilineage donor cell/progenitor expression with production of significant numbers of CD34+ cells. Secondary transplantation and limiting dilution studies confirmed the presence in human CD34− fraction of HSC with in vivo long‐term engraftment and multilineage differentiation potentials.
Isolation of Stem Cell‐Specific cDNAs from Hematopoietic Stem Cell Populations
Authors: ORLIC DONALD , LAPRISE SHARI L. , CLINE AMANDA P. , ANDERSON STACIE M. , BODINE DAVID M.
Published: February 2006

Abstract: We have begun to isolate gene sequences that are specifically expressed in hematopoietic stem cells (HSCs). There are at least three fundamental requirements for the isolation of HSC‐specific transcripts. First, highly enriched populations of HSCs, and an HSC‐depleted cell population for comparison must be isolated. Secondly, the gene isolation procedures must be adapted to accommodate the small amounts of RNA obtained from purified HSCs. Finally, a defined screening strategy must be developed to focus on sequences to be examined in more detail. In this report, we describe the characterization of populations of HSCs that are highly enriched (Lin− c‐kitHI) or depleted (Lin− c‐kitNEG) of HSCs. We compared two methods for gene isolation, differential display polymerase chain reaction (DD‐PCR) and subtractive hybridization (SH), and found that the latter was more powerful and efficient in our hands. Lastly we describe the strategy that we have developed to screen clones for further study.
Signaling Domains of the βc Chain of the GM‐CSF/IL‐3/IL‐5 Receptor
Authors: OKUDA KEIKO , FOSTER ROSEMARY , GRIFFIN JAMES D.
Published: February 2006

Abstract: The granulocyte/macrophage colony‐stimulating factor (GM‐CSF)/interleukin‐3 (IL‐3)/IL‐5 receptors are a family of heterodimeric transmembrane proteins expressed by myeloid lineage cells. Each receptor has a unique ligand‐binding α chain and they share a common β chain (βc chain). Binding of GM‐CSF activates at least one receptor‐associated tyrosine kinase, JAK2, and rapidly induces tyrosine phosphorylation of the GMR βc chain (GMRβ), but not the GMR αchain (GMRα). Mutation of each of the 8 tyrosine residues in the cytoplasmic domain of the human GMRβ to phenylalanine (GMRβF8) reduced tyrosine phosphorylation of GMRβ, SHP2 and SHC, but not JAK2 or STAT5. Interestingly, GMRβ‐F8 was still capable of inducing at least short‐term proliferation and enhancing viability. The role of each individual tyrosine residue was explored by replacing each mutated phenylalanine with the wild‐type tyrosine residue. Tyrosine 577 was found to be sufficient to regenerate GM‐CSF‐dependent phosphorylation of SHC, and any of Y577, Y612, or Y695 were sufficient to regenerate GM‐CSF‐inducible phosphorylation of SHP2. Next, a series of four internal deletion mutants were generated, which deleted small sections from aa 518 to 626. One of these, deleting residues 566‐589 was profoundly defective in signaling and supporting viability, and may identify an important viability signaling domain for this receptor family. Overall, these results indicate that GMRβ tyrosine residues are not necessary for activation of the JAK/STAT pathway, or for proliferation, viability, or adhesion signaling in Ba/F3 cells, although tyrosine residues significantly affect the magnitude of the response. However, internal deletion mutant studies identify critical domains for viability and proliferation.
Thrombopoietin and Hematopoietic Stem Cell Development
Authors: KAUSHANSKY KENNETH
Published: February 2006

Abstract: Thrombopoietin, the long sought primary regulator of thrombopoiesis, was cloned four years ago. In addition to its fulfilling most, if not all, of the expected biological activities relating to megakaryocyte and platelet development, the availability of the recombinant hormone and reagents to characterize its receptor have allowed detailed investigation of additional biological activities. In cultures of purified populations of candidate stem cells, thrombopoietin supports the survival, and aubments the proliferation of hematopoietic stem cells when present together with interleukin‐3 or steel factor. The progeny of such cultures are not skewed in their developmental potential; colony‐forming cells of all lineages arise from thrombopoietion‐stimulated stem cells. Evidence for an important effect of thrombopoietin on stem cell physiology in vivo are equally compelling. Genetic elimination of thrombopoietin or its receptor leads to a profound reduction not only of megakaryocytes and platelets, but also of committed myeloid progenitors of all types, primitive progenitors and hematopoietic stem cells. When administered to animals, thrombopoietin profoundly stimulates thrombopoiesis and enhances the number of hematopoietic progenitor cells of all lineages, and when used in most animal models of myelosuppressive therapy, accelerates the recovery of platelet, erythrocyte and leukocyte production. Thus, thrombopoietin appears to be more than a lineage‐restricted growth factor.
The Placental/Umbilical Cord Blood Program of the New York Blood Center A Progress Report
Authors: RUBINSTEIN PABLO , ADAMSON JOHN W. , STEVENS CLADD
Published: February 2006

Abstract: The transplantation of placental/umbilical cord blood (P/CB) has been used successfully to reconstitute bone marrow function in both related and unrelated recipients. We report here the experience of the New York Blood Center P/CB Program. Since its inception in 1992, over 400 unrelated transplants were supported between July 1993 and September 1997. Overall, event‐free survival for all diagnoses and ages approached 0.45. Success and rapidity of engraftment correlated most strongly with the degree of human leukocyte antigen (HLA) disparity and cell dose/kg body weight recipient. Acute graft‐versus‐host disease (GVHD) was common in all patients but, surprisingly, did not differ between those patients who received grafts having one or more antigen mismatches. Chronic GVHD was uncommon and only rarely contributed to death. These results demonstrate the feasibility of large‐scale P/CB banking for the provision of cryopreserved stem cell preparations for unrelated transplants. The degree of the program's success argues strongly for additional P/CB banks in order to increase the likelihood of finding a suitable stem cell preparation for patients for whom related matched donors do not exist.
The Role of Megadose CD34+ Progenitor Cells in the Treatment of Leukemia Patients without a Matched Donor and in Tolerance Induction for Organ Transplantation
Authors: REISNER YAIR , BACHAR‐LUSTIG ESTHER , LI HONG‐WEI , AVERSA FRANCO , VELARDI ANDREA , MARTELLI MASSIMO F.
Published: February 2006

Abstract: Throughout the 1980s, transplantation of unmodified (T cell‐replete) bone marrow from full haplotype incompatible family donors was associated with an unsuccessful outcome because of graft failure and severe graft‐versus‐host disease (GVHD), at times affecting up to 90% of recipients. Although extensive T cell depletion of donor bone marrow was successful in preventing GVHD in children with severe combined immunodeficiency disease (SCID), results were disappointing in leukemic patients because the benefit of preventing GVHD was offset by graft failure. Resistance to engraftment appears to be mediated by host‐derived cytotoxic T‐lymphocyte precursors that survive supralethal conditioning. In the present paper, we review data that show that these genetic histocompatibility barriers can be overcome in stringent mouse models, employing lethally as well as sublethally irradiated recipients, by two major approaches that are synergistic to each other: escalation of hematopoietic progenitor cell dose and the use of nonalloreactive T cells. The former approach is already being successfully implemented in the treatment of leukemic patients.
Transplantation of Megadoses of Purified Haploidentical Stem Cells
Authors: HANDGRETINGER R. , SCHUMM M. , LANG P. , GREIL J. , REITER A. , BADER P. , NIETHAMMER D. , KLINGEBIEL T.
Published: February 2006

Abstract: Peripheral mobilized parental CD34+ progenitors were isolated and used for the hematopoietic reconstitution after a myeloablative therapy in 23 pediatric patients with various diseases. Fourteen donors were human leukocyte antigen (HLA) three‐loci mismatches, 6 donors were two‐loci and 3 donors were one‐locus mismatches. For depletion of T‐lymphocytes, a positive selection of the mobilized peripheral CD34+ progenitors using the method of magnetic‐activated cell sorting (MACS) was used. The purity of the CD34+ cells after MACS‐sorting was 98‐99%, the average number of transplanted CD34+ cells was 14.2 3 × 106/kg (range 5.4‐3 9 × 3 I 06/kg) and the average number of infused T‐lymphocytes was 1.4 × 3 104/kg. Due to this low T cell number, only a short‐term or no prophylaxis of graft‐versus‐host disease (GVHD) was necessary and no GVHD was seen. A significant GVHD was only seen in patients after add‐back of donor T‐lymphocytes, which was performed in some patients for prevention of relapse or in patients who showed a transient mixed chimerism. Since the B lymphocyte contamination of the isolated CD34+ cells was low in the range of 0.2%, no Epstein‐Barr virus (EBV)‐associated lymphoproliferative syndrome was observed. A primary engraftment was seen in 18 patients. Nonengraftment and rejection occurred in three and two patients, respectively. In four of these 5 patients, a second transplant using purified CD34+ cells from the same donor after an immunological reconditioning regimen resulted in a complete and sustained hematopoietic reconstitution. The speed of the immunological recovery was dependent on the number of transplanted CD34+ cells and was more rapid if this number was >20 × 3 106/kg. Eleven of the 23 patients are alive and disease free with a median follow‐up of 12 months (range 2‐30). The main cause of death was relapse (7 patients), and only one fatal infection was seen. Our data suggest that the transplantation of megadoses of haploidentical CD34+ cells is a realistic therapeutic option for patients who otherwise have no suitable donor, and an alternative to the use of unrelated cord blood.
Approaches to Dendritic Cell‐Based Immunotherapy after Peripheral Blood Stem Cell Transplantation
Authors: BRUGGER W. , BROSSART P. , SCHEDING S. , STUHLER G. , HEINRICH K. , REICHARDT V. , GRÜNEBACH F. , BÜHRING H.‐J. , KANZ L.
Published: February 2006

Abstract: High‐Dose chemotherapy with peripheral blood progenitor cell transplantation (PBPCT) is a potentially curative treatment option for patients with both hematological malignancies and solid tumors, including breast cancer. However, based on a number of clinical studies, there is strong evidence that minimal residual disease (MRD) persists after high‐dose chemotherapy in a number of patients, which eventually results in disease recurrence. Therefore, several approaches to the treatment of mrd are currently being evaluated, including treatment with dendritic cell (DC)‐based cancer vaccines. DCs, which play a crucial role with regard to the initiation of T‐lymphocyte responses, can be generated ex vivo either from CD34+ hematopoietic progenitor cells or from blood monocytes. They can be pulsed in vitro with tumor‐derived peptides or proteins, and then used as a professional antigen‐presenting cell (APC) vaccine for the induction of antigen‐specific T‐lymphocytes in vivo. This paper summarizes our preclinical studies on the induction of primary HER‐2/neu specific cytotoxic T‐lymphocyte (CTL) responses using peptide‐pulsed DC. As HER‐2/neu is overexpressed on 30‐40% of breast and ovarian cancer cells, this novel vaccination approach might be particularly applicable to advanced breast or ovarian cancer patients after high‐dose chemotherapy and autologous PBPCT.
Mixed Hematopoietic Chimerism after Marrow Allografts Transplantation in the Ambulatory Care Setting
Authors: STORB RAINER , YU CONG , SANDMAIER BRENDA M. , MCSWEENEY PETER A. , GEORGES GEORGE , NASH RICHARD A. , WOOLFREY ANN
Published: February 2006

Abstract: This paper describes the development of nonmyeloablative marrow transplant programs that have little toxicity in a canine model and their translation to patients with malignant and nonmalignant hematological diseases.
Radiation Sterilization of a Bifunctional Cement Formulation of Hydroxilapatite‐Plaster‐Polymers
Authors: VIDAL DIANELYS SAINZ , NAPOLES DANIA RODRIGUEZ , ESTEVEZ GASTON FUENTES , GUERRA MERCEDES , SORIANO WILLIAMS ARCIS , AVES EDUARDO PEON , ARGOTA JOSE M. DIAZ , SILVA DIONISIO ZALDIVAR
Published: February 2006

ABSTRACT: A sterilization method based on the use of gamma ionizing radiation was applied to a cement formulation of hydroxilapatite, plaster and polymers to be used in bone restorations in dental, aesthetic, and neurological surgery. After the cement was exposed to a dose of 21.5 kGy it reached the sterility assurance level which was necessary for its employment in surgical applications as specified by International Standard ISO ordinate 11137: Radiation Sterilization of Health Care Products. No variation in the initial cement composition or processing parameters, such as working or setting time and molding quality was observed due to sterilization. Its characteristics as a drug delivery system were also not affected. Therefore, radiation sterilization provides a feasible alternative to conventional sterilization methods such as dry/wet heat and ethylene oxide.
Artificial Cells, Encapsulation, and Immobilization
Authors: MING SWI Chang THOMAS
Published: February 2006

ABSTRACT: The basic principles of artificial cells, encapsulation and immobilization form the asisS for a number of bioartificial organs. Hemoperfusion based on encapsulated adsorbent has been in routine clinical uses for many years to remove toxins or drugs from the circulating blood. Blood substitutes based on crosslinked hemoglobin or encapsulated hemoglobin are being developed and tested in phase II and Phase III clinical trials. Enzyme therapy using microencapsulated enzymes have been studied in animal studies and in a preliminary human study. encapsulation or other ways of immobilization of cells are being developed extensively by many groups. This includes the encapsulation or immobilization of islets, hepatocytes and genetically engineered cells.
Physico‐chemical and Mass Transfer Considerations in Microencapsulation
Authors: GOOSEN MATTHEUS F. A.
Published: February 2006

ABSTRACT: To gian better insight into mass transfer problems in encapsulated cell systems requires a combination of experimental investigations and mathematical modeling. Specific mass transfer studies are reviewed including oxygen transfer in immobilized animal cell culture bioreactors, modeling of polymer droplet formation and encapsulated animal cell growth, and growth of somatic tissue encapsulated in alginate using electrostatics. Special emphasis is given to electrostatic droplet generation for cell immobilization.
New Multicomponent Capsules for Immunoisolation
Authors: BARTKOWIAK ARTUR , CANAPLE LAURENCE , CEAUSOGLU ION , NURDIN NATHALIE , RENKEN ANDREAS , RINDISBACHER LORENZ , WANDREY CHRISTINE , DESVERGNE BÉATRICE , HUNKELER DAVID
Published: February 2006

ABSTRACT: A new generation of microcapsules based on the use of oligomers which participate in polyelectrolyte complexation reactions has been developed. These freeze‐thaw stable capsules have been applied as a bioartificial pancreas and have resulted in normoglycemia for periods of six months in concordant xenotransplantations. The new chemistry permits the control of permeability and mechanical properties over a wide range and can be adapted both to microcapsule and hollow fiber geometries rendering it a robust tool for encapsulation in general. Methods, and metrics, for the characterization of the mechanical properties and permeability of microcapsules are presented.
Encapsulation for Somatic Gene Therapy
Authors: CHANG PATRICIA L.
Published: February 2006

ABSTRACT: With the human genome project approaching its completion date of 2005, gene‐based technology will play an increasingly important role in health‐care delivery. Non‐autologous somatic gene therapy is a novel application in which non‐autologous cell lines engineered to secrete a recombinant protein are enclosed within immunoisolation devices and implanted into all patients requiring the same product for therapy. The development of this technology requiers a multi‐disciplinary effort towards optimization of the biomaterial used to manufacture the implantable devices and selection of the aporopriate cell lines for enclosure. The efficacy of this technology is illustrated in the treatment of dwarfism and lysosomal storage disease in murine models. The potential of a safe and cost‐effective gene‐based delivery method should have wide applications in treating both classical genetic disorders and non‐mendelian diseases.
Review‐The Use of Immunosuppressive Agents to Prevent Neutralizing Antibodies Against a Transgene Product
Authors: POTTER MURRAY A. , CHANG PATRICIA L.
Published: February 2006

ABSTRACT: A potential obstacle to successful gene therapy for some patients is the in vivo production of neutralizing antibodies against the recombinant therapeutic product delivered. This is a problem inherent to all gene therapy methods, regardless of the vector used to deliver the protein. This clinical situation can be mimicked in animal models by delivering a foreign protein (i.e., a human protein) to the animal to provoke anti‐human protein antibody production. The efficacy of different immunosuppressive treatments to inhibit the development of neutralizing antibodies can then be investigated. The immunosuppressive agents examined here include drugs (e.g., cyclophosphamide, FK506), cytokines (e.g., interferon‐γ, interleukin‐12), and monoclonal antibodies (e.g., anti‐CD4, anti‐gp39, CTLA4‐Ig). It has been found that a high level of antibody suppression is necessary to allow prolonged delivery of a foreign protein. Immunosuppressive agents capable of this high level of suppression will be important adjuncts to prevent treatment failures in situations where patients are at risk of developing neutralizing antibodies.
Clinical Islet Transplantation: A Review
Authors: OBERHOLZER JOSÉ , TRIPONEZ FRÉDÉRIC , LOU JINNING , MOREL PHILIPPE
Published: February 2006

ABSTRACT: For decades, the inability of insulin therapy to physiologically control glycemia in type I diabetic patients has motivated the search for insulin‐delivering grafts. Islet autotransplantation is such a therapeutic approach to prevent diabetes mellitus following a major pancreatectomy, whereas allo‐transplantation is generally prescribed for type I diabetic patients with a functional solid organ graft, or for patients awaiting one. As of today, over 150 patients have been autotransplanted world‐wide, following total or subtotal pancreatectomy, permitting an insulin‐independence in nearly 40% of patients. Furthermore, more than 350 islet allotransplantations have been performed. Recent results show improved metabolic control in over 50% of cases and insulin‐independence in approximately 20%. This chapter presents a literature review including preliminary human islet transplantation data from the University of Geneva.
Bioartificial Pancreas: Alternative Supply of Insulin‐secreting Cells
Authors: ZHOU DAOBIAO , KINTSOURASHVILI EKATERINA , MAMUJEE SALIM , VACEK IVAN , SUN ANTHONY M.
Published: February 2006

ABSTRACT: In this study, insulin secretion function of INS‐1 cells immunoisolated in microcapsules was evaluated. Following encapsulation, the immunoisolated INS‐1 cells continued to propagate and flourish within the microcapsules during the entire two‐month in vitro incubation period. The insulin secretion from encapsulated INS‐1 cells following seven days of in vitro culture increased from 1.6 ± 0.2 ng/2H/106 cells in a glucose‐free medium to 11.5 ± 2.1 ng/2h/106 cells at 16.7 mM glucose.

In vivo, transplants of 1.2 × 107 cells into each of six diabetic C57BL/6 mice resulted in the restoration of normoglycemia in all graft recipients for up to 60 days post transplantation. most capsules recovered from two animals 30 days post tarnsplantation were free of cell overgrowth and physically intact. Immunostaining for insulin of the cells within the recovered capsules clearly indicated the presence of insulin.

The presented data demonstrate the potential use of an immunoisolated β‐cell line for the treatment of diabetes.