bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural Capital and Labor Allocation
Authors: Barbier Edward B.
Published: November 2007

Many poor rural households exploit natural resources, and losses in natural capital may affect their participation in outside employment. The analysis of this article confirms that both mangrove area and the type of mangrove-dependent activity pursued by coastal households in Thailand have significant influences on the participation decision of adult males and females, the wages that they receive for outside employment, and the number of hours worked. Controlling mangrove deforestation could reduce the negative impacts on household labor allocation, but it will require a new institutional framework for coastal mangrove management inducing cooperation between government and coastal households. Investments in female education and training could improve their outside employment prospects and wage rates.
A Note on the Ethical Implications of the Stern Review on the Economics of Climate Change
Authors: Kenny Charles
Published: November 2007

The Stern Review on the economics of climate change adopts two interesting elements in its calculation of the costs and benefits of climate change mitigation. First is a “global-welfarist” approach that values the utility of the world's people (now and into the future) equally and sets global utility maximization as the correct goal for policy. Second is an assumption of a declining marginal utility to income. Consistent application of the global-welfarist approach and the declining marginal utility of income together would demand an urgent process of global income redistribution. In the long term, this might see the richest 10% of the world's population facing an average redistributive tax rate in the region of 82%.
Social Capital and Natural Resource Management
Authors: Ballet Jérôme , Sirven Nicolas , Requiers-Desjardins Mélanie
Published: November 2007

This article explores the reasons why community-based natural resource management is not necessarily a panacea. One reason may be that the communitarian benefits associated with social capital formation generally focus on the structural approach (e.g., network connections, group size) and too rarely take into consideration the underlying cultural context in which these relationships are embedded. Using Bourdieu's seminal framework for the different forms of capital (social, cultural, and symbolic), it indeed appears that (a) social capital is costly to produce and (b) its outcomes on resource management depend highly on the cultural capital (values, norms, etc.) in which it exists. The reference to Bourdieu's social capital helps to introduce the analysis of power relationships in community-based natural resource management.
Developing Long-Term Physical Activity Participation: A Grounded Theory Study With African American Women
Authors: Harley Amy E. , Buckworth Janet , Katz Mira L. , Willis Sharla K. , Odoms-Young Angela , Heaney Catherine A.
Published: November 2007

Regular physical activity is linked to a reduced risk of obesity and chronic disease. African American women bear a disproportionate burden from these conditions and many do not get the recommended amount of physical activity. Long-term success of interventions to initiate and maintain a physically active lifestyle among African American women has not been realized. By clearly elucidating the process of physical activity adoption and maintenance, effective programming could be implemented to reduce African American women's burden from chronic conditions. In-depth interviews were conducted with physically active African American women. Grounded theory, a rigorous qualitative research method used to develop theoretical explanation of human behavior grounded in data collected from those exhibiting that behavior, was used to guide the data collection and analysis process. Data derived inductively from the interviews and focus groups guided the development of a behavioral framework explaining the process of physical activity evolution.
Politics as the Church's Business: William Temple's Christianity and Social Order Revisited
Authors: Brown Malcolm
Published: November 2007

Christianity and Social Order was a creature of its time and, although influential over several decades, is challenged by today's plurality and globalization. Nevertheless, the ascendancy of Radical and Neo-Orthodoxy repeats imbalances of the Christendom Group which Temple was concerned to counter. Temple's greatest weakness for today is his failure to appreciate the trend towards profound social plurality, and its challenge to his strong idea of nationhood. However, today's global economy suggests that plurality must be held in tension with other aspects of the dominant market model. Temple's work reinforces important critiques of market economics, including scepticism about the alleged impossibility of moral agreement. This in turn suggests that total abandonment of Temple's Middle Axiom approach may be premature. A better-developed theology of correctives would reflect classic Christian vocabulary, cohere with Temple's approach, and offer a route toward the revitalization of the Anglican tradition of public theology.
Grace and Nation: Coleridge's On the Constitution of Church and State
Authors: Gregory Alan
Published: November 2007

Understanding Coleridge's classic work On the Constitution of Church and State requires paying close attention to the system of distinctions and relations he sets up between the state, the ‘national church’, and the ‘Christian church’. The intelligibility of these relations depends finally on Coleridge's Trinitarianism, his doctrine of ‘divine ideas’, and the subtle analogy he draws between the Church of England as both an ‘established’ church of the nation and as a Christian church and the distinction and union of divinity and humanity in Christ. Church and State opens up, in these ‘saving’ distinctions and connections, important considerations for the integrity and role of the Christian church within a religiously plural national life.
The Genetic Basis of Myeloproliferative Disorders
Authors: Skoda Radek
Published: November 2007

For many decades, myeloproliferative disorders (MPD) were largely neglected orphan diseases. The conceptual work of William Dameshek in 1951 provided the basis for understanding MPD as a continuum of related syndromes, possibly with a common pathogenetic cause. Recognition of the clonal origin of peripheral blood cells in MPD in 1976 and the ability to grow erythroid colonies in vitro in the absence of added growth factors in 1974 initiated the search for genetic alterations that might be responsible for myeloproliferation. Mutations in the genes for the erythropoietin receptor, thrombopoietin and the von Hippel–Lindau protein were found to cause familial syndromes resembling MPD, but despite their phenotypic similarities, none of these mutations were later found in patients with the sporadic form of MPD. The discovery of activating mutations in the Janus kinase 2 (JAK2) in most patients with MPD has fully transformed and energized the MPD field. Sensitive assays for detecting the JAK2-V617F mutation have become an essential part of the diagnostic work-up, and JAK2 now constitutes a prime target for developing specific inhibitors for the treatment of patients with MPD. Despite this progress, many questions remain unsolved, including how a single JAK2 mutation causes three different MPD phenotypes, what other genes might be involved in the pathogenesis, and what are the factors determining the progression to acute leukemia.
Novel Thrombopoietic Agents
Authors: Andemariam Biree , Psaila Bethan , Bussel James B.
Published: November 2007

Thrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with chemotherapy. There is a need for additional means to treat thrombocytopenia in these settings. Recombinant thrombopoietin-like agents became available after the cloning of thrombopoietin in 1994. In clinical trials, these agents showed some efficacy in chemotherapy-induced thrombocytopenia, but their use was ultimately discontinued due to the development of neutralizing antibodies that cross-reacted with endogenous thrombopoietin and caused thrombocytopenia in healthy blood donors and other recipients. Subsequently, “second-generation” thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical development and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C–related thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist’s ability to manage these and other causes of thrombocytopenia.
TTP and ADAMTS13: When Is Testing Appropriate?
Authors: Mannucci Pier Mannuccio , Peyvandi Flora
Published: November 2007

The last 10 years witnessed the publication of many studies on the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure. The most important finding was the identification of a novel metalloprotease, named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motives), that is involved in the regulation of the size of von Willebrand factor (VWF), a major modulator of platelet adhesion and aggregation in the microcirculation. Inherited or acquired deficiencies of ADAMTS13 impair VWF cleavage, leading in turn to the disseminated formation of platelet-rich thrombi in the micro-circulation and to symptoms of end-organ ischemia. By measuring ADAMTS13 in plasma, it has been clearly shown that patients with inherited TTP have severe ADAMTS13 deficiency. However, patients with acquired TTP present with clinical and laboratory heterogeneity, and there are unequivocal cases of acquired TTP with measurable plasma levels of ADAMTS13. This heterogeneity poses a challenge for understanding the pathogenesis of TTP and selecting appropriate therapies.
Management of Pregnant Women with Thrombophilia or a History of Venous Thromboembolism
Authors: Bates Shannon M.
Published: November 2007

Pregnancy is associated with an increased risk of venous thromboembolism (VTE), and this condition remains an important cause of maternal morbidity and mortality. Approximately 50% of gestational VTE are associated with thrombophilia. Recent studies suggest that there is also a link between thrombophilia and pregnancy loss, as well as other gestational vascular complications. Although the most compelling data derive from women with antiphospholipid antibodies, the use of anticoagulation for prevention of these complications in women with heritable thrombophilia is becoming more frequent. This article reviews the management and prevention of VTE and other complications related to the heritable thrombophilias during pregnancy, an area that remains particularly challenging because of the potential for anticoagulant-related fetal as well as maternal complications and the paucity of good-quality data upon which to base clinical decisions.
Management of Thrombohemorrhagic Syndromes (THS) in Hematologic Malignancies
Authors: Falanga Anna , Rickles Frederick R.
Published: November 2007

The rate of venous thromboembolism (VTE) in patients with acute leukemia or lymphomas is comparable with that of other “high-risk” cancer types. Chemotherapy and anti-angiogenic drugs increase the thrombotic risk in patients with lymphomas, acute leukemias and multiple myeloma (MM). Patients with hematologic malignancies often present with a hypercoagulable state or chronic disseminated intravascular coagulation (DIC) in the absence of active thrombosis and/or bleeding. Malignant cell procoagulant properties, cytotoxic therapies, and concomitant infections are major determinants for clotting activation in hematologic malignancies. In acute leukemia, clinical manifestations range from localized venous or arterial thrombosis to a diffuse, life-threatening thrombohemorrhagic syndrome (THS). All-trans retinoic acid (ATRA) has greatly improved the management of acute promyelocytic leukemia (APL), but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis. Randomized, controlled trials (RCTs) of different prophylactic regimens to prevent VTE or THS in hematologic malignancies are urgently needed, particularly in patients with lymphoma or MM during chemotherapy and in patients with APL. Anticoagulant therapy is a particular challenge in patients with hematologic malignancies, since these patients are at very high risk for hemorrhage. No guidelines are available for the prophylaxis or treatment of VTE; extrapolations can be made from existing guidelines for management of patients with other malignancies; prolonged periods of treatment-induced thrombocytopenia in patients with hematologic malignancies, however, require a more judicious application of standard anticoagulant approaches. Use of the newer anticoagulants will require careful assessment of hemorrhagic risk in this group of high-risk patients but may be justified under special circumstances.
Towards the Generation of Patient-Specific Pluripotent Stem Cells for Combined Gene and Cell Therapy of Hematologic Disorders
Authors: Daley George Q.
Published: November 2007

Hematopoietic stem cell transplantation (HSCT) has proven successful for the treatment of a host of genetic and malignant diseases of the blood, but immune barriers to allogeneic tissue transplantation have hindered wider application. Likewise, gene therapy now appears effective in the treatment of various forms of immune deficiency, and yet insertional mutagenesis from viral gene transfer has raised safety concerns. One strategy for addressing the limitations of both gene therapy and allogeneic transplantation entails the creation of pluripotent stem cells from a patient’s own somatic cells, thereby enabling precise in situ gene repair via homologous recombination in cultured cells, followed by autologous tissue transplantation. In murine model systems, the methods of somatic cell nuclear transfer, parthenogenesis, and direct somatic cell reprogramming with defined genetic factors have been used to generate pluripotent stem cells, and initial efforts at therapeutic gene repair and tissue transplantation suggest that the technology is feasible. Generating patient-specific autologous pluripotent stem cells provides an opportunity to combine gene therapy with autologous cell therapy to treat a host of human conditions. However, a number of technical hurdles must be overcome before therapies based on pluripotent human stem cells will appear in the clinic.
The Biology of the Germinal Center
Authors: Natkunam Yasodha
Published: November 2007

The immune system requires the production of high affinity antibodies of different subclasses to accomplish its many effector functions. Specific steps in B-cell ontogeny that occur within germinal centers of secondary lymphoid organs create much of the diversity in the immune system. This process also provides the raw material for the genesis of B-cell lymphomas as misdirection of the molecular machinery that regulate these steps can cause chromosomal translocations, prevent apoptosis and promote proliferation of abnormal clones. Many recent avenues of investigation have elucidated that the germinal center is a dynamic microenvironment where B-cells undergo repeated rounds of mutation and selection. Gene expression studies have further shown that malignancies derived from germinal center B-cells elaborate specific gene expression signatures that derive from neoplastic cells as well as elements of the host response such as T-cells and macrophages. This review will examine the current understanding of B-cell development in the germinal center and the key molecules involved in this process. Interactions between lymphoma cells and their cellular partners and models in the growth and development of follicular lymphoma will be presented.
Follicular NHL: From Antibodies and Vaccines to Graft-versus-Lymphoma Effects
Authors: Maloney David G.
Published: November 2007

Monoclonal antibody therapy with rituximab in combination with standard chemotherapy has improved the survival of patients with advanced-stage follicular lymphoma (FL). A series of next-generation anti-CD20 antibodies may be less immunogenic and have even greater antitumor activity through augmented interactions with host effector mechanisms responsible for tumor cell kill. Additional approaches with patient-specific immunoglobulin idiotype vaccines; novel monoclonal antibodies binding to biologically active cell-surface antigen are also demonstrating early clinical activity. Antibodies targeting radioisotopes, toxins or drugs are also slowly entering clinical trials and practice. Last, allogeneic stem cell transplantation following reduced-intensity conditioning provides graft-versus-tumor immune responses that may be able to control FL and allow this risky but potentially curative treatment option to older patents or those with comorbidities.
Vaccine Therapy for B-Cell Lymphomas: Next-Generation Strategies
Authors: Neelapu Sattva S. , Kwak Larry W.
Published: November 2007

Active immunotherapy is a promising approach for the treatment of lymphomas. Immunization with the clonal tumor immunoglobulin, idiotype, expressed on the surface of B-cell malignancies was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival in early clinical trials. Idiotype vaccination was also demonstrated to induce tumor-specific T-cell immunity in the absence of B cells following treatment with rituximab-containing chemotherapy, suggesting that vaccines may be used in combination with rituximab. Three double-blind randomized phase 3 idiotype vaccine trials are currently ongoing to definitively determine the clinical benefit of idiotype vaccination in patients with lymphoma. Novel second-generation lymphoma vaccines are in development to streamline the production of patient-specific cancer vaccines and show encouraging results in preclinical and pilot clinical studies. To enhance the clinical efficacy of active immunotherapy, future clinical trials are likely to use a combination strategy with the lymphoma vaccine to stimulate an antitumor T-cell response and the simultaneous suppression of immune regulatory pathways to augment the induced T-cell response.
Engineering Antitumor Immunity by T-Cell Adoptive Immunotherapy
Authors: Riddell Stanley R.
Published: November 2007

The adoptive transfer of antigen-specific T cells has been used successfully to treat experimental tumors in animal models and viral infections in humans, but harnessing the exquisite specificity and potency of T cells to treat human malignancy has proven challenging. The efforts to use T cells to treat patients with cancer have often been informative in identifying limitations that must be overcome to improve therapeutic efficacy, and a clearer picture of the requirements for successful adoptive T-cell transfer is gradually emerging. Indolent and a subset of aggressive B-cell lymphomas in humans have been shown to be susceptible to eradication by T cells in clinical settings where highly immunogenic minor histocompatibility or viral antigens are presented by tumor cells. In this article, we will review how recent advances in our understanding of the properties of antigen-specific T cells that facilitate their long-term persistence in vivo and reversion to the memory pool after in vitro culture, combined with approaches to molecularly engineer T cells with receptors that target molecules expressed by B-cell lymphoma, are providing opportunities to broaden the application of T-cell therapy and improve its efficacy for this disease.
Burkitt Lymphoma: Revisiting the Pathogenesis of a Virus-Associated Malignancy
Authors: Kelly Gemma L. , Rickinson Alan B.
Published: November 2007

Burkitt lymphoma (BL), a tumor occurring in endemic, sporadic and AIDS-associated forms, is the classic example of a human malignancy whose pathogenesis involves a specific cellular genetic change, namely, a chromosomal translocation deregulating expression of the c-myc oncogene, complemented in many cases by the action of an oncogenic virus, the Epstein-Barr virus (EBV). Here we review recent work in two complementary areas of research: (1) on cellular genetic changes that occur in addition to the c-myc translocation in BL, in particular the capacity of p53/ ARF pathway breakage or of c-myc mutation to decouple the pro-proliferative effects of c-myc deregulation from its pro-apoptotic effects; and (2) on a postulated role for EBV in BL pathogenesis, through adopting restricted forms of virus latent gene expression that remain compatible with the c-myc–driven growth program but offer the tumor additional protection from apoptosis. We stress the many fundamental questions that remain to be resolved and, in that regard, highlight the general lessons that might be learned through understanding how two other infectious agents, malaria and HIV, dramatically enhance BL incidence.
Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma
Authors: Reiter Alfred
Published: November 2007

Major advances have been made in the treatment of childhood non-Hodgkin lymphoma (NHL). The recognition that different NHL subtypes require different treatment strategies was fundamental to developing successful therapy regimens. Currently established therapy groups are lymphoblastic lymphoma (LBL) of precursor B- or T-cell type, mature B-cell neoplasms (B-NHL), and anaplastic large cell lymphoma (ALCL). Accurate diagnostic classification is crucial for allocating patients to appropriate treatment groups. Therapy protocols designed to treat children with acute lymphoblastic leukemia (ALL) have proven highly efficacious for treating children with LBL and are associated with event-free survival (EFS) rates up to 80%. For children with B-NHL, a strategy of rapidly repeated short, dose-intense courses proved more efficacious, with EFS rates up to 90%. In patients with ALCL, comparable results are achieved with either strategy, although this group has the highest relapse rate. The price of these efficacious treatments is considerable toxicity. On the other hand, the chance to survive after relapse is still dismal due to the almost complete lack of established salvage regimen. Thus, refinement of the balance between treatment burden and individual patient risk for failure is a major future task. A variety of new treatment options, some already established for treating adult NHL, await evaluation in childhood NHL.
Navigating the Evolving Paradigms in the Diagnosis and Treatment of Myeloproliferative Disorders
Authors: Mesa Ruben A.
Published: November 2007

The diagnosis and management of the BCR-ABL–negative myeloproliferative disorders (MPDs) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are at an explosive crossroads of scientific investigation and evolving paradigms since the discovery of the tyrosine kinase–activating JAK2V617F mutation in 2005. Additional discovery of relevant molecular lesions (JAK2 exon 12 mutations and c-MplW515L/K) have only further enriched our understanding of MPD pathogenesis. The improved diagnostic certainty these molecular markers provide have resulted in the modification, and simplification, of the World Health Organization (WHO) diagnostic algorithms for MPDs. Despite these scientific advances, however, the initial management of MPDs continues to rely upon a risk-based strategy to minimize the risk of vascular events with control of erythrocytosis, targeted antiplatelet therapy, and risk-based myelosuppressive therapy. No current medical therapy has altered the natural trend of the MPDs to lead to overt severe myelofibrosis or acute leukemia. Investigations into targeted therapies for MPDs are proceeding at a brisk pace with agents aimed at immunomodulation, decreasing marrow stromal reaction to the aberrant clone, DNA hypomethylation, or the inhibition of tyrosine kinases. Specific inhibition of JAK2 itself appears promising by in vitro investigations, and clinical trials with multiple agents are planned to commence enrollment in 2007. The potential impact of JAK2 inhibitors on the manifestations of the MPDs is unclear, but is awaited with great interest.
Medical Management of CML
Authors: Shah Neil P.
Published: November 2007

Management strategies of patients with chronic-phase chronic myeloid leukemia (CML) have been revolutionized by the BCR-ABL–selective kinase inhibitor imatinib, which is substantially improving median survival. However, a proportion of patients suffer progressive disease on imatinib therapy. Importantly, patients who are particularly at risk for developing progressive disease can be identified with appropriate monitoring of disease burden. Many of these patients may benefit from alternative treatment strategies, including second-generation kinase inhibitors such as dasatinib. As a result of improvements in medical therapy, allogeneic stem cell transplantation is increasingly deferred despite its known curative potential. It is anticipated that outcomes with medical therapy will continue to improve with the availability of effective second- and third-generation kinase inhibitors, and the percentage of patients progressing to the advanced phase of the disease is projected to decline. The future of kinase inhibitor therapy for CML may involve combinations of ABL kinase inhibitors.
Chronic Myeloid Leukemia: Molecular Monitoring in Clinical Practice
Authors: Branford Susan
Published: November 2007

The role of molecular monitoring for patients with chronic myeloid leukemia (CML) is multifaceted. Milestone measurements up to 18 months of first-line imatinib therapy are prognostic and provide warning signals of suboptimal response. Serial measurements for patients with a complete cytogenetic response determine ongoing treatment efficacy or signal pending relapse. The pattern of molecular and cytogenetic response is generally comparable, but only cytogenetic analysis can monitor for the acquisition of clonal abnormalities and has an important role in case of loss of molecular response. For patients treated with imatinib, a rising level of BCR-ABL is a trigger for kinase domain mutation analysis. The characterization of BCR-ABL inhibitor-resistant mutations is important to direct therapeutic intervention because it is now apparent that each resistant mutation functions as a distinct protein with unique biological properties that may confer a gain or loss of function. The benefit to patients of regular molecular analysis is a reassurance of ongoing response using the most sensitive of techniques or a potential improvement in outcome for those where relapse is indicated early. However, despite the obvious benefits of molecular analysis, the measurement techniques may not be quite ready for acceptance into the routine clinical monitoring practices of all clinicians. The challenge now is to standardize and simplify the method so that it can be readily and reliably incorporated into routine laboratory testing procedures.
Management of RBC-Transfusion Dependence
Authors: Melchert Magda , List Alan F.
Published: November 2007

Strategies for the management of anemia in patients with myelodysplastic syndrome (MDS) have evolved following the U.S. Food and Drug Administration (FDA) approval of three new therapeutics from one of symptom amelioration with red blood cell (RBC) transfusions to one of active treatment. Most patients develop transfusion-dependent anemia over the course of their disease, however, and its adverse consequence on the natural history of disease has only recently been appreciated. Although severe anemia contributes to symptoms of fatigue and reduced quality of life, transfusion dependence increases the risk of organ complications from iron overload coupled with an increased risk of leukemia transformation. Among World Health Organization categories without elevation in bone marrow myeloblasts, an incremental rise in RBC transfusion burden is associated with a proportionate reduction in both overall survival and leukemia-free survival, implying that anemia severity is an important variable limiting the otherwise favorable natural history of patients with lower risk disease. Moreover, therapeutic strategies that successfully restore effective erythropoiesis, such as erythropoetic stimulating agents, immunomodulatory agents, immunosuppressive therapies, or hypomethylating agents, may favorably affect the natural history of this disease, creating perhaps a new urgency for the initiation of erythropoietic promoters that have durable clinical benefit. Selection of primary therapy for the management of anemia should consider four response determinants: age, RBC transfusion burden and duration, endogenous erythropoietin production, and karyotype.
Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion
Authors: Lazarus Hillard M. , Luger Selina
Published: November 2007

The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia (ALL) is not clear-cut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in complete remission (CR). Those considered to be at high risk for relapse often are considered for HSCT in first complete remission (CR1) while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor. In some patients who have a suitable histocompatible sibling, disease- or patient-related factors may override the potential benefit of allogeneic HSCT. Because many patients do not have a suitable histocompatible sibling, one has to consider the relative merits of autologous transplantation versus use of an alternative allogeneic stem cell source, such as a matched-unrelated donor (MUD), umbilical cord blood (UCB) donor, or haploidentical donor. Deciding among these options in comparison to chemotherapy even in high-risk patients is difficult. In the review, the risks and benefits of these choices are discussed to determine whether and by what means to proceed to HSCT in adult patients with ALL who are in CR1. Presented are two patients with ALL and a discussion of how the data we provide would lead to a decision about the selection of therapy.
Reduced-Intensity Stem Cell Transplantation
Authors: Antin Joseph H.
Published: November 2007

The recognition that the immune system can play a major role in the control and cure of transplantable disorders led to the development of reduced-intensity allogeneic transplantation. The notion is that a compromise can be made between the intensity of conditioning and the fostering of graft-versus-host disease/ graft-versus-leukemia (GVHD/GVL), allowing the use of less intense conditioning with concomitantly less intense immediate toxicity. Reduced-intensity conditioning regimens have allowed the application of transplantation to older patients and to patients with underlying medical problems that preclude full-dose transplantation. Clearly, in some settings in which dose intensity is important, reduced-intensity regimens are less useful. However, for diseases that are either indolent, highly susceptible to GVL, or under good control before entering transplantation, this approach appears to have substantial benefits. Although the therapy appears to be valuable, concerns about delayed immune reconstitution and GVHD remain.
RNAi and Gene Therapy: A Mutual Attraction
Authors: Grimm Dirk , Kay Mark A.
Published: November 2007

The phylogenetically conserved cellular phenomenon of RNA interference (RNAi)—the sequence-specific post-transcriptional silencing of gene expression mediated by small double-stranded RNAs—holds substantial promise for basic research and for drug development. Particularly attractive from a medical standpoint is the juxtaposition of new RNAi methodology with established gene transfer strategies, especially viral vectors for efficient and tissue-specific RNAi delivery to patients. Here, we summarize the latest experimental and clinical advances in RNAi-based gene therapy approaches. We briefly portray emerging nonviral strategies for siRNA transfer, before comparing the three viral vectors currently predominantly developed as shRNA delivery vehicles, adenovirus, lentivirus, and adeno-associated virus (AAV). Moreover, we describe the most clinically relevant genetic, acquired or infectious targets being pursued for therapeutic purposes. Specifically, we assess the use of vector-mediated RNAi for treatment of viral processes, solid cancers, lymphoproliferative disorders, and neurodegenerative and ocular diseases. In addition, we highlight further emerging applications, including stem cell therapies and animal transgenesis, as well as discuss some of the potential pitfalls and limitations inherent to the individual approaches. While we predict that eventual schemes will be shaped by our increasing understanding of the complexities of human RNAi biology, as well as by progressive refinements of viral shuttle designs, the potential scientific and medical benefits from a successful marriage of RNAi and gene therapy seem enormous.
Are There Circumstances in Which Phase 2 Study Results Should Be Practice-Changing?
Authors: Tomblyn Marcie R. , Rizzo J. Douglas
Published: November 2007

New pharmaceuticals, innovative combinations of approved agents, and novel treatment modalities have resulted in a marked increase in the need for clinical trials. Evidence for treatment efficacy is best derived from large phase 3 randomized, controlled clinical trials. However, phase 3 investigations are lengthy and expensive, and consume patient resources. Furthermore, some diseases and treatment indications are rare, and adequate numbers of patients for a definitive phase 3 trial do not exist. Consequently, it is imperative for clinicians to understand phase 2 trial design, since their interpretation is required to apply the findings in clinical practice appropriately. The complexity of phase 2 studies is explored, including unique designs, possible use of randomization, and other key elements necessary for interpretation of phase 2 trials. Specific examples and application of these concepts are discussed in this review.
Umbilical Cord Blood (UCB) Transplantation: An Alternative to the Use of Unrelated Volunteer Donors?
Authors: Barker Juliet N.
Published: November 2007

Cryopreserved umbilical cord blood (UCB) from 4-6/6 HLA-A,B antigen and DRB1 allele matched unrelated neonatal donors contains sufficient numbers of hematopoietic stem cells (HSC) to engraft most younger pediatric patients with leukemia. Recent data demonstrate promising results in larger children and adults, as well as in patients with nonmalignant disorders. As a result, the number of UCB transplantations (UCBT) being performed is increasing dramatically. UCB has the clear benefits of rapid availability and a reduced stringency of requirement for HLA match. The latter attribute has the potential to extend the donor pool, which is of great importance for racial and ethnic minorities. Furthermore, new preparative regimens combined with double-unit grafts have been associated with improved engraftment and survival in larger children and adults, making UCBT a viable potential alternative to unrelated volunteer donor transplantation, especially in preference to transplantation using mismatched volunteers. This review summarizes the current status of unrelated donor UCBT and describes both the challenges and current areas of research associated with this HSC source.
Hemoglobin E Syndromes
Authors: Vichinsky Elliott
Published: November 2007

Hemoglobin (Hb) E is one of the world’s most common and important mutations. It results in a heterogeneous group of disorders whose phenotype range from asymptomatic to severe. Hb E trait and Hb EE are mild disorders. The combination of Hb E and Hb S (Hb SE) results in a sickle cell disease syndrome similar to sickle β+ thalassemia. It is important to distinguish Hb E disorders diagnostically because of this marked difference in clinical course among different genotypes. Screening tests, including hemoglobin electrophoresis and high-pressure liquid chromatography (HPLC), may suggest other mutations, unless one is familiar with the findings. E β-thalassemia, the most serious form of E syndromes, affects a million people worldwide and is increasing in North America. Its phenotype ranges from mild anemia to severe transfusion-dependent thalassemia major. Several genetic modifiers affect the phenotype, including the type of β-thalassemia mutation, Hb F levels, and co-inheritance of α-thalassemia. However, the cause of the phenotypic variability is largely unknown. A prospective natural history study of E β-thalassemia in Sri Lanka suggests that environmental modifiers are prognostically important. The clinical course of E β-thalassemia is punctuated by acute and chronic complications that may cause serious morbidity and mortality. Recent studies indicate these patients are at high risk for thromboembolism secondary to a hypercoagulable state increased by splenectomy. Morbidity from iron overload in nontransfused patients secondary to increased gastrointestinal iron absorption is common. Cardiopulmonary disease, including pulmonary hypertension, requires ongoing monitoring and is secondary to iron overload, thromboembolism, and hemolysis-induced nitric oxide deficiency. These patients are excellent candidates for Hb F–modulating agents because moderate changes in hemoglobin may result in marked improvement in phenotype. Recent studies with hydroxyurea indicate 40% of patients will clinically improve with hydroxyurea.
Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease
Authors: Telen Marilyn J.
Published: November 2007

A number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.
The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition
Authors: Chng Wee J. , Braggio Esteban , Mulligan George , Bryant Barbara , Remstein Ellen , Valdez Riccardo , Dogan Ahmet , Fonseca Rafael
Published: November 2007

Centrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression–based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G2-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.
Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma
Authors: Chauhan Dharminder , Singh Ajita , Brahmandam Mohan , Podar Klaus , Hideshima Teru , Richardson Paul , Munshi Nikhil , Palladino Michael A. , Anderson Kenneth C.
Published: November 2007

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib–induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-κB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib–treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.
CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer
Authors: Garçon Fabien , Patton Daniel T. , Emery Juliet L. , Hirsch Emilio , Rottapel Robert , Sasaki Takehiko , Okkenhaug Klaus
Published: November 2007

Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen-presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Using a quantitative imaging-based assay, we show that the PI3K activity at the T cell–APC contact area is dependent on the p110δ, but not the p110γ, isoform of PI3K. CD28 enhanced PIP3 production at the T-cell synapse independently of its YMNM PI3K-recruitment motif that instead was required for efficient PKCθ recruitment. CD28 could partially compensate for the lack of p110δ activity during T-cell activation, which indicates that CD28 and p110δ act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110δ double-deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutic targeting of p110δ activity and CD28 costimulation has potent therapeutic potential.
Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke
Authors: Pruissen D. Martijn O. , Slooter Arjen J. C. , Rosendaal Frits R. , van der Graaf Yolanda , Algra Ale
Published: November 2007

Prothrombotic conditions are associated with ischemic stroke in young women. In particular, the combination of oral contraceptive use and prothrombotic genetic variants appears to increase the risk of ischemic stroke. We performed a population-based case-control study in 190 women aged 20 to 49 years with ischemic stroke and 767 women without cardiovascular disease stratified for age, calendar year of the index event, and residence. A total of 4 variants of coagulation factor XIII subunit A and B genes (F13A1 and F13B) were investigated. The Phe allele of the F13A1 Tyr204Phe variant was present in 59 (31%) patients and 43 (6%) controls; the odds ratio for ischemic stroke was 9.1 for Phe/Phe and Phe/Tyr versus Tyr/Tyr genotype; the 95% confidence interval was 5.5 to 15. Homozygous genotypes (Phe/Phe) conferred a higher risk (odds ratio, 77; 95% confidence interval, 7.0-848) than heterozygous (Tyr/Phe) genotypes (odds ratio, 8.2; 95% confidence interval, 4.9-14). The risk of ischemic stroke was further increased in carriers of the 204Phe allele using oral contraceptives (odds ratio, 20; 95% confidence interval, 9-46) compared with nonusers with Tyr/Tyr genotype. In conclusion, the F13A1 204Phe allele was strongly associated with ischemic stroke in young women. Oral contraceptive use further increased the risk of ischemic stroke.
Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency
Authors: Józsi Mihály , Licht Christoph , Strobel Stefanie , Zipfel Svante L. H. , Richter Heiko , Heinen Stefan , Zipfel Peter F. , Skerka Christine
Published: November 2007

Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of factor H–related proteins CFHR1 and CFHR3 as predisposing factor for aHUS. Here we identify in an extended cohort of 147 aHUS patients that 16 juvenile individuals (ie, 11%) who either lacked the CFHR1/CFHR3 completely (n = 14) or showed extremely low CFHR1/CFHR3 plasma levels (n = 2) are positive for factor H (CFH) autoantibodies. The binding epitopes of all 16 analyzed autoantibodies were localized to the C-terminal recognition region of factor H, which represents a hot spot for aHUS mutations. Thus we define a novel subgroup of aHUS, termed DEAP HUS (deficiency of CFHR proteins and CFH autoantibody positive) that is characterized by a combination of genetic and acquired factors. Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option.
LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1
Authors: Rastelli Julia , Hömig-Hölzel Cornelia , Seagal Jane , Müller Werner , Hermann Andrea C. , Rajewsky Klaus , Zimber-Strobl Ursula
Published: November 2007

The Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell–specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.