bluuebunny/crossref_metadata_2025_split huggingface dataset:
Update on Supportive Care and New Therapies: Immunomodulatory Drugs, Growth Factors and Epigenetic-Acting Agents
Authors: Hellström-Lindberg Eva 
Published: November 2005

Abstract
Patients with “low-risk” myelodysplastic syndrome (MDS) are mostly treated with approaches aiming to reduce the negative consequences of ineffective hematopoiesis. Transfusion therapy should be tailored to allow adequate oxygenation and optimal quality of life, and may lead to the need for iron chelation therapy. Growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF]) may induce long-lasting improvement of hemoglobin levels and does not increase the risk for leukemic transformation. Growth factors should be offered to defined subgroups of patients. Immunosuppression with anti-thymoglobulin or cyclosporine A may be an alternative for younger patients with refractory anemia (RA). The new immunomodulating compound lenalidomide, CC5013, is very active in the 5q– syndrome and is under evaluation for other low-risk MDS subtypes. “High-risk” MDS is associated with poor survival and high risk for leukemic transformation. The DNA hypomethylating compounds azacytidine and decitabine may offer improved long-term outcomes in this group of patients, although there has so far been no effect on survival rates. The efficacy of farnesyl transferase inhibitors has been evaluated in a series of phase II trials. The overall response rate was low, but the majority of responses were CRs. Finally, a number of new drugs directed to various biological and genetic targets are entering clinical trials.
Pathobiology of Lymphoid and Myeloid Blast Crisis and Management Issues
Authors: Ilaria Robert L. 
Published: November 2005

AbstractDespite recent improvements in the treatment of early-stage disease, the blastic phase of chronic myeloid leukemia (CML) remains a therapeutic challenge. For imatinib-naïve patients, imatinib provided encouraging hematologic and cytogenetic benefits; however, the vast majority of CML blast crisis cases today arise in patients already on imatinib-based therapy. Clonal evolution and duplication of the Philadelphia chromosome continue to be associated with blastic phase transformation, but recent studies have identified BCR/ABL kinase domain mutations in 30%–40% of blast crisis patients. This implies that BCR-ABL–targeted therapy might have influenced the molecular road map to blastic transformation. In this review, we will examine the effect of imatinib on primitive CML progenitors and how this might influence the pathophysiology of blast crisis. A rational framework for deciding how best to integrate stem cell transplantation, traditional chemotherapy, imatinib, and other BCR-ABL kinase inhibitors in the care of blast crisis patients will also be discussed.
Red Cell Enzymes
Authors: Prchal Josef T. , Gregg Xylina T. 
Published: November 2005

AbstractMutations leading to red cell enzyme deficiencies can be associated with diverse phenotypes that range from hemolytic anemia, methemoglobinemia, polycythemia, and neurological and developmental abnormalities. While most of these mutations occur sporadically, some such as common glucose-6-phosphate dehydrogenase (G6PD) mutants are endemic and rarely cause disease. Common G6PD mutants likely reached their prevalence because they provide some protection against severe malarial complications. In this review G6PD, pyruvate kinase, 5′ nucleotidase, and cytochrome b5 reductase deficiencies will be discussed in greater detail. Limitations of commonly used screening tests for detection of these disorders will also be emphasized, as well as emerging knowledge about non-enzymatic function of the glycolytic enzymes.
Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer
Authors: Shore Gordon C. , Viallet Jean 
Published: November 2005

AbstractMembers of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.
Immunobiology and Pathophysiology of Hodgkin Lymphomas
Authors: Poppema Sibrand 
Published: November 2005

Abstract
Classical Hodgkin lymphoma (HL) is characterized by the presence of Reed-Sternberg (RS) cells, which are transformed post-germinal center B cells destined for apoptosis since they have not undergone successful immunoglobulin gene rearrangement. Several mechanisms, including latent infection by Epstein-Barr virus (EBV), allow these cells to survive. It is remarkable that many of the signaling pathways that promote survival are shared between the EBV-induced proteins, such as EBNA1, LMP1, and LMP2, and other molecules that are upregulated in RS cells. A key role is played by the presence of constitutive nuclear factor (NF)-κB, which is induced by LMP1, as well as by CD30, CD40, tumor necrosis factor (TNF)-α, and Notch1 interactions, and results in the upregulation of at least 45 genes including chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors. The other characteristic of classical HL is the presence of an extensive inflammatory infiltrate. Key features of this infiltrate are that it comprises Th2 and T regulatory cells and generally lacks Th1 cells, CD8 cytotoxic T cells, and natural killer (NK) cells. The RS cells appear to induce this infiltrate by the secretion of Th2 type chemokines such as TARC and MDC. The RS cells also produce cytokines that inhibit Th1 responses, as interleukin (IL)-10 and transforming growth factor (TGF)-β express CD95 ligand, which induces apoptosis of activated Th1 and CD8 T cells. Other important mechanisms that allow the RS cells to escape an effective anti-EBV immune response include the downregulation of HLA class I in EBV-negative cases or the presence of a polymorphism in HLA class I in EBV-positive cases that allow escape from CD8-mediated cytotoxicity. On the other hand, expression of HLA-G allows the escape from NK cells that would normally recognize the HLA class I-negative RS cells. Overall, the cellular infiltrate in HL appears to play a decisive role in allowing the RS cells to survive by providing an environment that suppresses cytotoxic immune responses and providing cellular interactions and cytokines that support the growth and survival of RS cells. Future therapeutic strategies could focus directly on the NF-κB activation, on various receptors to ligand interactions, on the chemokine and cytokine network, or on the induction of effective anti-EBV latent protein immune responses.
Therapies for Relapsed Hodgkin Lymphoma: Transplant and Non-Transplant Approaches Including Immunotherapy
Authors: Bartlett Nancy L. 
Published: November 2005

AbstractAutologous stem cell transplant remains the standard of care for relapsed Hodgkin lymphoma (HL). Approximately 50% of patients with chemo-sensitive relapse will be cured with this approach. The optimal pretransplant salvage regimen is controversial, but less toxic combinations seem to be equivalent to more aggressive approaches. For patients with chemo-refractory disease at relapse and those failing autologous transplant, the long-term prognosis remains poor. New approaches such as reduced-intensity allogeneic transplant, monoclonal antibodies targeting the CD30 antigen, Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes, and bortezomib are under investigation, but preliminary results are disappointing. New therapies are needed for patients with relapsed HL.
Biology and Treatment of Epstein-Barr Virus–Associated Non-Hodgkin Lymphomas
Authors: Heslop Helen E. 
Published: November 2005

AbstractEpstein-Barr virus (EBV) is associated with several different types of aggressive non-Hodgkin lymphoma (NHL). Individuals with primary or secondary immunodeficiency are susceptible to developing B cell lymphoproliferation due to outgrowth of EBV-infected B cells that express type III latency characterized by expression of all nine latent-cycle EBV antigens. These cells would normally be susceptible to control by EBV-specific T cells, and strategies to restore EBV-specific immune responses may be effective therapeutically. EBV-associated lymphomas occurring in individuals who do not have a known immunodeficiency include NK and T malignancies with cytotoxic phenotypes, sporadic cases of B-NHL and lymphomatoid granulomatosis. These malignancies respond poorly to standard chemoradiotherapy, and immunotherapeutic or pharmacologic strategies targeting EBV are being explored.
Salvage Therapy for CLL and the Role of Stem Cell Transplantation
Authors: Gribben John G. 
Published: November 2005

Abstract
Chronic lymphocytic leukaemia (CLL) remains an incurable disease and, notwithstanding the excellent remission rates now achieved with purine analogs and monoclonal antibodies, the vast majority of patients with CLL are destined to relapse after primary treatment. The management of relapsed CLL patients is then dependent upon a number of factors, most importantly age, performance status, previous therapy administered, the response and duration of response to such therapy, and time from last therapy. Although prior therapy and response to such therapy are important factors in determining next therapy, it is often difficult to determine their importance from published studies. Furthermore, the goal of therapy, whether palliative or aggressive, must also be weighed into the decision when deciding on the next line of treatment. With many potential treatments available, the sequence of treatments and the timing of procedures such as stem cell transplantation remain controversial and are the focus of ongoing clinical trials.
Hematopathology Approaches to Diagnosis and Prognosis of Indolent B-Cell Lymphomas
Authors: Gascoyne Randy D. 
Published: November 2005

AbstractThe advent of new technologies has contributed to improvements in the diagnosis and classification of the non-Hodgkin lymphomas (NHL). Use of a more extensive test menu of paraffin active monoclonal antibodies for immunohistochemistry, molecular cytogenetic studies including standard cytogenetics, multi-color fluorescence in-situ hybridization (FISH), polymerase chain reaction and locus-specific FISH, as well as developments in high-resolution techniques including microarray gene expression profiling and array comparative genomic hybridization (CGH) allow more accurate diagnosis and precise definition of biomarkers of value in risk stratification. The identification of disease-specific gene lists resulting from expression profiling provides a number of potential protein targets that can be validated using immunohistochemistry. We will highlight how improvements in our understanding of lymphoma biology rapidly facilitate the development of new diagnostic reagents that could be used to alter clinical practice. These changing trends allow the development of new diagnostic strategies used to render accurate sub-classification of entities within the category of indolent B-cell lymphomas, including their distinction from related but more aggressive disorders, such as mantle cell lymphoma. A comprehensive understanding of the biology of these distinct lymphoid tumors will allow us to identify novel disease-related genes and should facilitate the development of improved diagnostics, outcome prediction, and personalized approaches to treatment.
Pathophysiology of β Thalassemia—A Guide to Molecular Therapies
Authors: Thein Swee Lay 
Published: November 2005

Abstract
The central mechanism underlying the pathophysiology of the β thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the α/non-α globin chains leads to an excess of unmatched α globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the α/non-α chain imbalance. They include inheritance of the milder forms of β thalassemia, co-inheritance of α thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing γ globin expression. Currently, the most promising molecular therapeutic approaches include increasing β globin gene expression by stem cell gene therapy and increasing γ globin expression using pharmacological agents or by transduction of the γ globin genes.
Multimodality Therapies and Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example
Authors: Ghielmini Michele 
Published: November 2005

AbstractRituximab was the first humanized antibody widely used on patients, so research on its optimal use was a clinical challenge. Many studies have been performed to optimize its dose and schedule, and more are ongoing. The dose of 375 mg/m2 has become standard, mainly because it shows activity and has little associated toxicity. The combination of rituximab with chemotherapy has been shown to prolong remission in all types of lymphomas, and in patients with diffuse large B-cell lymphoma it can improve survival. As a single agent, particularly when the treatment is prolonged over several months, results are similar to chemotherapy but with fewer side effects. Finally, used as maintenance therapy it can prolong the duration of chemotherapy-obtained remissions. Based on available data, the administration of 375 mg/m2 before each chemotherapy cycle can be recommended for first line treatment of patients with curable B-cell lymphomas and for patients with high-risk indolent lymphoma who are rituximab-naïve. Single-agent treatment at a prolonged schedule is recommended for cases of indolent disease not in need of urgent response and for patients who are unlikely to tolerate chemotherapy.
Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy
Authors: Friedberg Jonathan W. 
Published: November 2005

Abstract
Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.
Reduced-Intensity Conditioning Regimens for Hematologic Malignancies: What Have We Learned over the Last 10 Years?
Authors: Giralt Sergio 
Published: November 2005

AbstractReduced-intensity conditioning (RIC) regimens have been investigated for more than 10 years as an alternative to traditional myeloablative conditioning regimens. RIC regimens are being commonly used in older patients as well as in disorders in which traditional myeloablative conditioning regimens are associated with high rates of non-relapse mortality. Hodgkin disease, myeloma, and low-grade lymphoid malignancies have been the diseases most impacted by RIC regimens. RIC regimens have also been shown to be safe and effective in older patients as well as patients with co-morbidities, although patients with chemorefractory disease still have high relapse rates and poor outcomes. Patients with chemosensitive disease have outcomes similar to those obtained with conventional ablative therapies, and thus comparative trials are warranted. RIC regimens are associated with lower rates of severe toxicity and non-relapse mortality; however, infections, graft-versus-host disease, and relapse of primary disease remain the most common obstacles to a successful outcome. The impact on survival and the relative benefits of RIC allografting compared with traditional conditioning regimens or alternative therapy remain to be defined. Incorporating targeted therapies as part of the conditioning regimens or as maintenance therapies is currently being explored to reduce relapse rates without increasing toxicity.
Inherited Platelet Disorders
Authors: Handin Robert I. 
Published: November 2005

Abstract
The inherited platelet disorders are a heterogeneous collection of rare diseases that are infrequently encountered in clinical practice. They are, however, fascinating abnormalities, which have taught us a great deal about normal platelet biochemistry and physiology. In this section of the presentation we will review disorders of the platelet membrane, platelet granule packaging disorders, the hereditary macrothrombocytopenias, platelet signaling disorders and disorders of platelet coagulant function. The molecular basis of the disorders, the cardinal features of their clinical presentation and best methods to make their diagnosis and the latest information regarding therapy will be presented.
The Cardiovascular Pharmacology of COX-2 Inhibition
Authors: Fries Susanne , Grosser Tilo 
Published: November 2005

AbstractSelective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI2) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A2, unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI2 oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA2. Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure.
Gene Therapy for β-Thalassemia
Authors: Malik Punam , Arumugam Paritha I. 
Published: November 2005

AbstractGene transfer for β-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of β globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human β-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus–based lentiviral (LV) vectors were shown to stably transmit the human β-globin gene and a large LCR element, resulting in correction of β-thalassemia intermedia in mice. Several groups have since demonstrated correction of the mouse thalassemia intermedia phenotype, with variable levels of β-globin expression. These levels of expression were insufficient to fully correct the anemia in thalassemia major mouse model. Insertion of a chicken hypersensitive site-4 chicken insulator element (cHS4) in self-inactivating (SIN) LV vectors resulted in higher and less variable expression of human β-globin, similar to the observations with cHS4-containing retroviral vectors carrying the human γ-globin gene. The levels of β-globin expression achieved from insulated SIN-LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with human thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo. In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley’s anemia and other β-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.
Evaluation of Hematopoietic Stem Cell Donors
Authors: Horowitz Mary M. , Confer Dennis L. 
Published: November 2005

Abstract
Donation of hematopoietic stem cells, either through bone marrow or peripheral blood collection, is a generally safe procedure for healthy donors. Serious adverse events are uncommon and death is exceedingly rare. Nevertheless, all donors must be carefully evaluated and fully informed prior to donation. This should be done by clinicians having good understanding of the potential physical and psychological complications of donation and the factors that may increase these risks. Additionally, donors and graft products must be evaluated for the potential to transmit infections and other diseases to the recipient and to satisfy an increasing number of national and international regulatory requirements. Donors must be able to provide informed consent without coercion or pressure. Special attention to the clinical, psychological and social needs of pediatric donors is necessary.