bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burkitt Lymphoma: Revisiting the Pathogenesis of a Virus-Associated Malignancy
Authors: Kelly Gemma L. , Rickinson Alan B. 
Published: November 2007

AbstractBurkitt 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

AbstractMajor 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

Abstract
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

AbstractManagement 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

Abstract
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

Abstract
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

AbstractThe 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

Abstract
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

AbstractThe 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

Abstract
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

AbstractCryopreserved 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

AbstractHemoglobin (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

AbstractA 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

AbstractCentrosome 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

AbstractOur 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

AbstractActivation 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.