bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of IFN-γ Signal Transduction Defects with Impaired HLA Class I Antigen Processing in Melanoma Cell Lines
Authors: Respa Annedore , Bukur Juergen , Ferrone Soldano , Pawelec Graham , Zhao Yingdong , Wang Ena , Marincola Francesco M. , Seliger Barbara 
Published: January 2011

AbstractPurpose: Abnormalities in the constitutive and IFN-γ–inducible HLA class I surface antigen expression of tumor cells is often associated with an impaired expression of components of the antigen processing machinery (APM). Hence, we analyzed whether there exists a link between the IFN-γ signaling pathway, constitutive HLA class I APM component expression, and IFN-γ resistance.Experimental Design: The basal and IFN-γ–inducible expression profiles of HLA class I APM and IFN-γ signal transduction cascade components were assessed in melanoma cells by real-time PCR (RT-PCR), Western blot analysis and/or flow cytometry, the integrity of the Janus activated kinase (JAK) 2 locus by comparative genomic hybridization. JAK2 was transiently overexpressed in JAK2− cells. The effect of IFN-γ on the cell growth was assessed by XTT [2,3-bis(2-methoxy-4-nitro-S-sulfophenynl)-H-tetrazolium-5-carboxanilide inner salt] assay.Results: The analysis of 8 melanoma cell lines linked the IFN-γ unresponsiveness of Colo 857 cells determined by lack of inducibility of HLA class I surface expression on IFN-γ treatment to a deletion of JAK2 on chromosome 9, whereas other IFN-γ signaling pathway components were not affected. In addition, the constitutive HLA class I APM component expression levels were significantly reduced in JAK2− cells. Furthermore, JAK2-deficient cells were also resistant to the antiproliferative effect of IFN-γ. Transfection of wild-type JAK2 into JAK2− Colo 857 not only increased the basal APM expression but also restored their IFN-γ sensitivity.Conclusions: Impaired JAK2 expression in melanoma cells leads to reduced basal expression of MHC class I APM components and impairs their IFN-γ inducibility, suggesting that malfunctional IFN-γ signaling might cause HLA class I abnormalities. Clin Cancer Res; 17(9); 2668–78. ©2011 AACR.
The Brain-Bone-Blood Triad: Traffic Lights for Stem-Cell Homing and Mobilization
Authors: Lapidot Tsvee , Kollet Orit 
Published: January 2011

Abstract
Navigation of transplanted stem cells to their target organs is essential for clinical bone marrow reconstitution. Recent studies have established that hematopoietic stem cells (HSCs) dynamically change their features and location, shifting from quiescent and stationary cells anchored in the bone marrow to cycling and motile cells entering the circulation. These changes are driven by stress signals. Bidirectional migrations to and from the bone marrow are active processes that form the basis for HSC transplantation protocols. However, how and why HSCs enter and exit the bone marrow as part of host defense and repair is not fully understood. The development of functional, preclinical, immune-deficient NOD/SCID (non-obese diabetic-severe combined immunodeficiency) mice transplantation models has enabled the characterization of normal and leukemic human HSCs and investigation of their biology. Intensive research has revealed multiple tasks for the chemokine SDF-1 (stromal cell-derived factor-1, also known as CXCL12) in HSC interactions with the microenvironment, as well as the existence of overlapping mechanisms controlling stress-induced mobilization and enhanced HSC homing, sequential events of major physiological relevance. These processes entail dynamically interacting, multi-system aspects that link the bone marrow vasculature and stromal cells with the nervous and immune systems. Neural cues act as an external pacemaker to synchronize HSC migration and development to balance bone remodeling via circadian rhythms in order to address blood and immune cell production for the physiological needs of the body. Stress situations and clinical HSC mobilization accelerate leukocyte proliferation and bone turnover. This review presents the concept that HSC regulation by the brain-bone-blood triad via stress signals controls the bone marrow reservoir of immature and maturing leukocytes.
The Past: What We Have Learned in the Last Decade
Authors: Borchmann Peter , Engert Andreas 
Published: January 2011

AbstractHodgkin lymphoma (HL) has become a curable malignancy for most patients during the last decades. However, many controversies still exist on the optimal strategy of how to cure our patients. The key question is how to balance the risks and toxicities of chemotherapy and radiotherapy against the need for a definite treatment for early or advanced-stage HL patients. However, although many studies have been conducted and reported during the past decade, interpretation of their results and treatment recommendations might vary significantly in different countries. For example, early-stage HL might be divided into two different subgroups: early favorable and early unfavorable or not. Treatment of early-stage HL might include radiotherapy (“combined modality”) or not. Depending on the extent of radiotherapy, the schedule and number of chemotherapy cycles are also questioned. For advanced-stage HL, the situation is not much different. Compared with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the more aggressive escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is highly effective, but also raises concern due to excessive toxicity. Thus, there is a controversy about the standard of care for advanced HL patients. Because no mature results comparing these approaches with each other are currently available, it remains our duty to share the preliminary information with our patients and to figure out the most appropriate individual treatment strategy. Of course, the discussion of these issues is influenced by experiences and preferences. In contrast, in this article, we will try to focus on the available scientific evidence regarding the first-line treatment of HL. Of course, focusing on the last decade necessarily exclude the most recent results from ongoing studies. Thus, even though this article comprises treatment recommendations for HL patients, the best treatment certainly still is within properly designed prospective clinical trials.
The Present: Optimizing Therapy—Too Much or Too Little?
Authors: Bartlett Nancy L. 
Published: January 2011

AbstractDespite the use of less toxic chemotherapy and more limited doses and fields of radiation, the prognosis for patients with all stages of classical Hodgkin lymphoma (HL) has continued to improve over the last 20 years. The challenge today is better identification of prognostic markers that will allow even further reduction of therapy in the most favorable subsets and new approaches for those who have a high risk of failure with current approaches. Most ongoing clinical trials for newly diagnosed HL base therapy decisions on the result of an interim restaging PET/CT, de-escalating for early responders and escalating for patients with a suboptimal response. While awaiting the results of these important trials, the debates rage on regarding the use of consolidative radiotherapy in early stage HL and the use of escalated BEACOPP in advanced stage disease. Unfortunately, we still face the very difficult decision with nearly every patient with HL of “too much,” risking long-term consequences, or “too little,” risking relapse and the need for additional toxic therapy. At present, we need to make these very difficult initial treatment decisions with inadequate data, but reassured by the excellent outcomes for most patients and encouraged by the new agents available for those who fail first-line therapy.
Assessing New Therapies and Their Overall Impact in Myelofibrosis
Authors: Mesa Ruben A. 
Published: January 2011

AbstractClinical management of myelofibrosis (MF)—whether primary or arising from an antecedent myeloproliferative neoplasm (post-essential thrombocythemia/polycythemia vera MF)—is currently in a period of transition that began with the discovery of the JAK2-V617F mutation 5 years ago. Selective JAK2 inhibitors have been developed, and clinical trials thus far have demonstrated that several of these agents meaningfully reduce MF-associated splenomegaly and constitutional symptoms. JAK2 inhibitors have durable benefits, act across the spectrum of MF subtypes, and provide a level of symptomatic benefit not seen with previous generations of nontargeted therapies. However, the JAK2 inhibitors can cause anemia and/or gastrointestinal disturbance, and their impact on JAK2 allele burden and the natural history is not yet fully defined. Several additional therapies that do not directly target JAK2 (eg, immunomodulatory drugs, histone deacetylase inhibitors, and inhibitors of the mammalian target of rapamycin [mTOR]) may ameliorate MF-associated anemia and morbidity-inducing symptoms. Balancing the potential benefits of these new agents against the risks and benefits of allogeneic stem cell transplantation (which can be curative, but carries a high risk of treatment-associated morbidity and mortality) requires an accurate estimation of the prognosis for an individual patient. Enhanced prognostic modeling systems are helping us to better characterize prognosis in MF patients not only at diagnosis, but also along the dynamic and variable course of the illness. Future advancements in the efficacy of MF-targeted therapy will likely arise from new pathogenetic insights and from combining JAK2 inhibitors with other agents.
Chronic Myeloid Leukemia 2010: Where Are We Now and Where Can We Go?
Authors: Radich Jerald P. 
Published: January 2011

Abstract
Chronic myeloid leukemia is a model of how the molecular understanding of a disease can provide the platform for therapy and diagnostics. Clinicians are now empowered with first- and second-generation tyrosine kinases, as well as molecular tools to monitor disease and characterize resistance. However, there are still unanswered questions regarding optimization of therapy, the utility of molecular monitoring, and the search (or need) of “cure” that bears thought. In this review, we will discuss these issues, as they provide a roadmap for what may lie ahead in the therapy of other hematologic malignancies, particular the other myeloproliferative syndromes, where specific genetic lesions, and targeted therapy, are now being realized.
Rethinking Disease Definitions and Therapeutic Strategies in Essential Thrombocythemia and Polycythemia Vera
Authors: Harrison Claire 
Published: January 2011

AbstractThe seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors.
Treating the “Older” Adult With Acute Lymphoblastic Leukemia
Authors: Marks David I. 
Published: January 2011

Abstract
Acute lymphoblastic leukemia (ALL) in adults is a rare disease. The results of therapy remain unsatisfactory, and progress has been relatively slow. This article will focus on curative therapy in patients aged 30 to 60 years, but will also discuss the management of elderly patients with ALL. Recent large trials have increased our knowledge of the factors that determine outcome, and have clarified the role of blood and marrow transplantation in the management of this disease. These trials have also highlighted the major issues we need to focus on if we are to improve outcomes. This article describes the results of chemotherapy and blood and marrow transplantation for Philadelphia chromosome negative and positive adult ALL in the “older” adult patient, but also critically examines the major controversies and suggests how they might be resolved. The role of allografting in adult ALL is comprehensively discussed. Results of recent studies on T-cell ALL and reduced-intensity allografting are reviewed. A better understanding of the biology of the disease (including gene profiling) may allow individualization of therapy and, in time, targeted therapy.
Thrombocytopenia in the Intensive Care Unit Patient
Authors: Greinacher Andreas , Selleng Kathleen 
Published: January 2011

Abstract
The many comorbidities in the severely ill patient also make thrombocytopenia very common (∼ 40%) in intensive care unit patients. The risk of bleeding is high with severe thrombocytopenia and is enhanced in intensive care patients with mild or moderately low platelet counts when additional factors are present that interfere with normal hemostatic mechanisms (eg, platelet function defects, hyperfibrinolysis, invasive procedures, or catheters). Even if not associated with bleeding, low platelet counts often influence patient management and may prompt physicians to withhold or delay necessary invasive interventions, reduce the intensity of anticoagulation, order prophylactic platelet transfusion, or change anticoagulants due to fear of heparin-induced thrombocytopenia. One approach to identify potential causes of thrombocytopenia that require specific interventions is to consider the dynamics of platelet count changes. The relative decrease in platelet counts within the first 3 to 4 days after major surgery is informative about the magnitude of the trauma or blood loss, whereas the dynamic of the platelet count course thereafter shows whether or not the physiologic compensatory mechanisms are working. A slow and gradual fall in platelet counts developing over 5 to 7 days is more likely to be caused by consumptive coagulopathy or bone marrow failure, whereas any abrupt decrease (within 1–2 days) in platelet counts manifesting after an initial increase in platelet counts approximately 1 to 2 weeks after surgery strongly suggests immunologic causes, including heparin-induced thrombocytopenia, other drug-induced immune thrombocytopenia, and posttransfusion purpura.
Thrombosis in Cancer: An Update on Prevention, Treatment, and Survival Benefits of Anticoagulants
Authors: Lee Agnes Y.Y. 
Published: January 2011

AbstractThromboembolism is a common, complex, and costly complication in patients with cancer. Management has changed significantly in the past decade, but remains firmly dependent on the use of anticoagulants. Low-molecular-weight heparin is the preferred anticoagulant for prevention and treatment, although its limitations open opportunities for newer oral antithrombotic agents to further simplify therapy. Multiple clinical questions remain, and research is focusing on identifying high-risk patients who might benefit from primary thromboprophylaxis, treatment options for those with established or recurrent thrombosis, and the potential antineoplastic effects of anticoagulants. Risk-assessment models, targeted prophylaxis, anticoagulant dose escalation for treatment, and ongoing research studying the interaction of coagulation activation in malignancy may offer improved outcomes for oncology patients.
Recombinant Factor VIIa: An Assessment of Evidence Regarding Its Efficacy and Safety in the Off-Label Setting
Authors: Logan Aaron C. , Goodnough Lawrence T. 
Published: January 2011

Abstract
Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. Prominent off-label indications include the management of patients with coagulopathies, such as occurs in trauma patients experiencing massive and uncontrolled hemorrhage, and in patients undergoing cardiovascular surgery with cardiopulmonary bypass. Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off-label setting.
Pregnancy and Commonly Used Drugs in Hematology Practice
Authors: Koren Gideon , Lishner Michael 
Published: January 2011

Abstract
When a woman suffering from a hematological condition is contemplating pregnancy, she may need to continue the use of medications that do not have sufficient evidence of fetal safety. We discuss the evidence existing for some therapies of major hematological conditions in the context of major principles in clinical teratology. It is critical to always balance the potential fetal risks of the drug in question against the maternal and fetal risks of the untreated hematological condition.
Consultative Hematology: The Pregnant Patient Pregnancy Loss
Authors: Bates Shannon M. 
Published: January 2011

Abstract
The presence of antiphospholipid antibodies has been associated with an increased risk of recurrent pregnancy loss, and there is evidence to suggest that antithrombotic therapy improves the likelihood of a successful outcome in affected women. Recent studies suggest an association between hereditary thrombophilia and pregnancy loss, although a causal role remains controversial. Although the available data are limited and flawed, there is increasing use of antithrombotic therapy in thrombophilic women with a history of pregnancy failure. Given the absence of proven effective therapy in women with unexplained recurrent loss, there is also growing pressure to intervene with antithrombotics in women with no known underlying thrombophilia. This article reviews the evidence for an association between thrombophilia and recurrent pregnancy loss and the data regarding the use of antithrombotic therapy for prevention of loss—an area that remains particularly challenging because of the paucity of good quality data upon which to base clinical decisions.
Evidence Base for the Management of Venous Thromboembolism in Pregnancy
Authors: Rodger Marc 
Published: January 2011

AbstractVenous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of maternal mortality during pregnancy. DVT and PE are commonly suspected due to many mimicking signs and symptoms that are normal in pregnancy. However, validated diagnostic approaches are lacking, and a fear of teratogenic/oncogenic exposure from imaging procedures affects the acceptability of diagnostic approaches used for VTE during pregnancy. DVT and PE treatment in pregnancy is also challenging due to this lack of validated diagnostic approaches, changes in maternal physiology, and the need for intact hemostasis at the time of delivery/epidural analgesia. Prevention requires an optimal balancing of absolute increased bleeding risk from pharmacologic thromboprophylaxis and the absolute benefit of reduced DVT and PE, which, while serious, are relatively uncommon.
Preparing Basic and Translational Grant Proposals: Thoughts from the Trenches
Authors: Molldrem Jeffrey J. 
Published: January 2011

Abstract
Written primarily for first-time applicants, this overview is a collection of tips intended to convey an approach to grant writing based on the experience of the author. Therefore, it is not a comprehensive review and it does not supplant the numerous treatises on grant writing, which cover everything from writing style and grammar to details regarding individual granting mechanisms and agencies. Rather, it is a brief overview of the grant writing process from conception to submission.
Tips for Writing Successful Patient-Oriented Research Career Development Awards
Authors: Lee Stephanie J. 
Published: January 2011

Abstract
Preparing a career development award can be an immensely satisfying experience and a great boost to a research career if successful, or it can seem like a miserable waste of time if unsuccessful. This paper highlights tips for the preparation of patient-oriented career development awards and provides references for grant-writing guidance. Patient-oriented research is defined as “research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator directly interacts with human subjects. This area of research includes: 1) mechanisms of human disease; 2) therapeutic interventions; 3) clinical trials, and; 4) the development of new technologies.”1
Hematology Grants Workshop
Authors: Williams David A. 
Published: January 2011

Abstract
In this yearly update on grant writing, we attempt to provide the attendee/reader with advice from “senior” investigators concerning the application process for external grant funds. While focused particularly on federal (National Institutes of Health, NIH) grants, the advice is generally applicable to any competitive grant-funding mechanism. Drs. Stephanie Lee and Jeffrey Molldrem have provided very thorough advice on clinical and basic grant applications and tips for those early in their careers. The session will include ample time for questions and answers, with key staffers from NIH in attendance.
The Aging Patient with Hemophilia: Complications, Comorbidities, and Management Issues
Authors: Philipp Claire 
Published: January 2011

AbstractImprovements in hemophilia care and antiviral treatments have resulted in increases in median life expectancy for persons with congenital hemophilia A and B. Currently, 2% of hemophilia A and B patients surveyed in US comprehensive hemophilia treatment centers are 65 years of age or older and 15% are 45 years or older. Many of the complications of hemophilia, including intracranial hemorrhage, joint disease, and inhibitor development, increase with increasing age. Hepatocellular carcinoma and end-stage liver disease are increasing in the older hemophilia population due to infection with hepatitis C (HCV) and HCV/HIV coinfection. Older hemophilia patients also now face the same medical conditions associated with aging in the general population, including cardiovascular disease and cancer. Complex hemostatic management, sometimes in conjunction with antithrombotic management, with extensive cross-specialty clinical and laboratory coordination may be required for the care of the older hemophilia patient. Because elderly hemophilia patients currently represent a small portion of the overall hemophilia population, there is little in the way of clinical data to guide recommendations. Registry databases and cooperative group studies are needed for the development of evidence-based guidelines for the older hemophilia population, which is anticipated to expand in the future.