bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inherited Neutrophil Disorders
Authors: Dinauer Mary C. , Lekstrom-Himes Julie A. , Dale David C. 
Published: October 2019

AbstractRecent advances in our understanding of the molecular basis of inherited neutrophil disorders and complementary studies in transgenic mouse models have provided new insights into the normal mechanisms regulating myelopoiesis and the functional responses of mature neutrophils. Neutrophil specific granule deficiency is a rare disorder of neutrophil function characterized by a lack of neutrophil secondary granule proteins and associated with recurrent bacterial infections. The CCAAT/enhancer binding protein (C/EBP) ϵ, a leucine zipper transcription factor expressed primarily in myeloid cells, and C/EBPϵ-deficient mice generated by gene targeting lack specific granules and have impaired host defense are discussed by Dr. Lekstrom-Himes in Section I. The similarity between these phenotypes led to the identification of a loss of function mutation in the C/EBPϵ gene in a subset of patients with specific granule deficiency. Dr. Dale reviews the clinical features and management of congenital neutropenia and cyclic hematopoiesis in Section II. Inherited mutations in the neutrophil elastase gene have recently been identified in both disorders. Specific mutations identified in cyclic and congenital neutropenia are described along with possible mechanisms for regulation of hematopoiesis by neutrophil elastase. In Section III, Dr. Dinauer reviews the molecular genetics of chronic granulomatous disease and studies in knockout mouse models. This work has revealed important features of the regulation of the respiratory burst oxidase and its role in host defense and inflammation. Results from preclinical studies and phase 1 clinical trials for gene therapy for CGD are summarized, in addition to alternative approaches using allogeneic bone marrow transplantation with nonmyeloablative conditioning.
Transfusion Medicine: New Clinical Applications of Cellular Immunotherapy
Authors: Brenner Malcolm , Rossig Claudia , Sili Uluhan , Young James W. , Goulmy Els 
Published: October 2019

There is now clear clinical evidence that adoptive cellular immunotherapy can eradicate hematologic malignancy and cure otherwise lethal viral infections. With this knowledge comes the challenge of improving the effectiveness and safety of the approach and of simplifying the methodologies required whilst still meeting appropriate federal regulatory guidelines. This review provides an overview of the current status of cellular immunotherapies and addresses how they may be implemented and the future directions they are likely to take.In Section I, Dr. Brenner with Drs. Rossig and Sili reviews the clinical experience to date with adoptive transfer of viral antigen-specific T cells for the successful treatment of Epstein-Barr virus-associated malignancies as well as viral infectious diseases. Genetic modification of the T cell receptor of the infused cells to potentiate such T cells as well as modifications to improve safety of the infusions are described.In Section II, Dr. Young describes the hematopoietic lineages of human dendritic cells and some of their immunotherapeutic applications. The critical importance of dendritic cells to T cell immunity and the capacity to generate dendritic cells in large numbers has spawned enormous interest in the use of these specialized leukocytes to manipulate cellular immunity. Successful cytokine-driven differentiation of dendritic cells reveal two types, myeloid- and plasmacytoid or lymphoid-related dendritic cells. The effects of maturation on phenotype and function of the dendritic cells and their use as immune adjuvants in dendritic cell vaccines to elicit antitumor and antiviral immunity are reviewed.In Section III, Professor Goulmy illustrates some current and future approaches towards tumor-specific cellular therapy of hematopoietic malignancy. Minor histocompatibility antigen (mHag) disparities between HLA-matched bone marrow donor and recipient can induce allo-responses that may participate in post bone marrow transplantation (BMT) graft-versus-leukemia (GVL) reactivities. A lack of such allo-reactivity may result in relapse of leukemia after BMT. In these patients, adoptive immunotherapy with cytotoxic T cells (CTLs) specific for hematopoietic system-restricted mHags may be used as an extension of current efforts using immunotherapy with donor lymphocyte infusions. Adoptive immunotherapy with CTLs specific for the hematopoietic system-restricted mHags, however, offers the prospect of greater and more predictable effectiveness in the absence of graft-versus-host disease.
Gene Therapy 2000
Authors: Williams David A. , Nienhuis Arthur W. , Hawley Robert G. , Smith Franklin O. 
Published: October 2019

Abstract
This article reviews 1) the use of gene transfer methods to genetically manipulate hematopoietic stem cell targets, 2) recent advances in technology that are addressing problems that have prevented widespread successful translation of gene transfer approaches for the cure of disease, and 3) recent regulatory issues related to human gene therapy trials.
In Section I, Dr. Nienhuis describes the use of alternative viral envelopes and vector systems to improve efficiency of transduction of hematopoietic stem cells. Major limitations of stem cell transduction are related to low levels of viral receptors on the stem cells of large animal species and the low frequency of cycling stem cells in the bone marrow. Attempts to circumvent these limitations by exploiting non-oncoretroviral vectors and pseudotyping of Moloney vectors with alternative envelopes are discussed.
In Section II, Dr. Hawley addresses new strategies to improve the expression of transgenes in cells derived from long-term reconstituting hematopoietic stem cells. Transgene silencing in transduced hematopoietic stem cells remains an obstacle to gene therapy for some gene sequences. New generations of retroviral backbones designed to both improve expression and reduce silencing in primary cells are explored.
In Section III, Drs. Smith and Cornetta update regulatory issues related to human gene therapy trials. Increased scrutiny of human trials has led to changes in requirements and shifts in emphasis of existing regulations, which apply to human gene therapy trials. The current Food and Drug Administration's structure and regulations and the roles of the Recombinant DNA Advisory Committee of the NIH and other sponsors and partners in gene therapy trials are reviewed.
New Developments in the Therapy of Acute Myelocytic Leukemia
Authors: Gorin Norbert C. , Estey Elihu , Jones Richard J. , Levitsky Hyam I. , Borrello Ivan , Slavin Shimon 
Published: October 2019

Current conventional treatment for patients with acute myelogenous leukemia results in a high percentage of clinical responses in most patients. However, a high percentage of patients still remain refractory to primary therapy or relapse later. This review examines the search for new agents and new modes of therapy. In Section I, Dr. Estey discusses new agents directed at various targets, such as CD33, angiogenesis, inappropriately methylated (suppressor) genes, cell cycle checkpoints, proteosomes, multidrug resistance (MDR) gene, mitochondrial apoptotic pathway. He also reviews preliminary results of phase I trials with the nucleoside analog troxacitabine and liposomal anthracyclin and suggests new strategies for trials of new agents.In Section II, Dr. Jones revisits differentiation therapy and presents results of preclinical and clinical studies that demonstrate that a variety of clinically applicable cell cycle inhibitors (interferon, phenylbutyrate, vitamin D, retinoids, bryostatin-1) preferentially augments growth factor-mediated induction of myeloid leukemia terminal differentiation, as well as blocks growth factors' effects on leukemia proliferation. The combination of cell cycle inhibition plus myeloid growth factors may offer a potential treatment for resistant myeloid leukemias.In Section III, Drs. Levitsky and Borrello address the question of tumor vaccination in AML and shows that, although tumor rejection antigens in AML have not been formally identified to date, a growing number of attractive candidates are ripe for testing with defined antigen-specific vaccine strategies. Interestingly, the ability to drive leukemic blasts to differentiate into competent antigen presenting cells such as dendritic cells may be exploited in the creation of cellular vaccines. Ultimately, the successful development of active immunotherapy for AML will require integration with dose-intensive chemotherapy, necessitating a more complete understanding of host immune reconstitution.In Section IV, Dr. Slavin reviews the concept of delivering non-myeloablative stem cell transplantation (NST) and delayed lymphocyte infusion (DLI) to increase tolerance in particular in high risk and older patients, and take advantage of the graft-versus-leukemia (GVL) effect.All these approaches hold promise in reducing morbidity and mortality and differ from the older concepts aiming at delivering the highest possible doses of chemotherapy and/or total body irradiation to reach maximum leukemia cell kill, whatever the toxicity to the patient.
Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies
Authors: Kantarjian Hagop , Melo Junia V. , Tura Sante , Giralt Sergio , Talpaz Moshe 
Published: October 2019

AbstractOver the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios.In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity.In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented.In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control.In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.
Hematology Grants Workshop
Authors: Ferrara James L.M. , Schmaier Alvin H. 
Published: October 2019

Abstract
The process of writing an NIH grant application is complex and difficult. Understanding critical details of the review process is a key to success. In this article the authors analyze the NIH grant application process from the reviewer’s perspective. They discuss NIH review criteria and highlight the characteristics of successful grant applications. They also suggest specific strategies to improve applications in terms of timeliness, clarity, focus, and independence and cover the key elements to revising an application that is not funded initially.
Treatment of acute myeloid leukemia: are we making progress?
Authors: Burnett Alan K. 
Published: October 2019

Abstract
With a few subgroups as exceptions, such as younger patients with more favorable genetic disease, improvement in the treatment of acute myeloid leukemia has been slow. There is a possibility that improving the quality of remission can reduce the risk of relapse. Escalation of daunorubicin dose, addition of Ab-directed chemotherapy, and alternative nucleoside analogs in induction may displace the longstanding standard of “3 + 7” daunorubicin + cytarabine (Ara-C) as induction, and several prognostic factors are emerging that enable a more personalized approach to postinduction treatment, in particular, which patients should be offered allogeneic transplantation in first remission. In addition to providing prognostic information, molecular characterization provides potential therapeutic targets and, in some cases, an opportunity to more precisely monitor residual disease. With few exceptions, the predictive value of prognostic factors (ie, what therapy to adopt) has yet to be established. A major challenge is the treatment of older patients with acute myeloid leukemia (AML), who represent the majority of patients with this disease. Only about half of older AML patients will enter complete remission (CR) with conventional chemotherapy and, of these, most will relapse within 2 years. Little impact has been made on these dismal outcomes over the past 3 decades, and new treatments and approaches to trial design are required. Another population of concern is older AML patients who are not considered to be fit for an intensive approach based on concerns about their ability to withstand the consequences of treatment. This group is not easy to define objectively, but age represents a useful surrogate because it is associated with more chemoresistant disease and medical comorbidity. Older patients represent a therapeutic challenge, but several new treatments may offer some potential to improve their situation.
Initial choice of therapy among plenty for newly diagnosed chronic myeloid leukemia
Authors: Marin David 
Published: October 2019

Abstract
Imatinib has been the preferred initial therapy for newly diagnosed chronic myeloid leukemia patients for the past 10 years. Recently, other, possibly better, tyrosine kinase inhibitors have been licensed for first-line use based on the early results of 2 large, randomized clinical trials. The pros and cons of the various alternatives to imatinib are analyzed herein, and I try to answer the question of are we ready to abandon imatinib and, if yes, then what treatment should a patient diagnosed today receive.
Thrombocytopenia in pregnancy: is this immune thrombocytopenia or…?
Authors: Gernsheimer Terry B. 
Published: October 2019

Abstract
Thrombocytopenia is a common finding in pregnancy. Establishing the diagnosis of immune thrombocytopenia (ITP) in a pregnant patient is similar to doing so in a nonpregnant patient, except that the evaluation must specifically rule out other disorders of pregnancy associated with low platelet counts that present different risks to the mother and fetus and may require alternate distinct therapy. Many of the same treatment modalities are used to manage the pregnant patient with ITP, but others have not been determined to be safe for the fetus, are limited to a particular gestational period, or side effects may be more problematic during pregnancy. The therapeutic objective differs from that in chronic ITP in the adult because many pregnant patients recover or improve spontaneously after delivery and therefore maintenance of a safe platelet count, rather than prolonged remission, is the goal. Thrombocytopenia may the limit choices of anesthesia, but does not guide mode of delivery, and the fetus is rarely severely affected at birth. Patients should be advised that a history of ITP or ITP in a previous pregnancy is not a contraindication to future pregnancies and that, with proper management and monitoring, positive outcomes can be expected in the majority of patients.
Are we making progress in GVHD prophylaxis and treatment?
Authors: Pavletic Steven Z. , Fowler Daniel H. 
Published: October 2019

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective immunotherapy for human cancer. More than 20 000 allo-HCTs are performed each year worldwide, primarily for the treatment of hematologic malignancies. Several technical innovations implemented in allo-HCT over past 2 decades have reduced NRM by 50% and improved overall survival. The allo-HCT practice has changed with the introduction of peripheral blood, cord blood, and haploidentical transplantations and reduced-intensity conditioning, and the patient population is also different regarding age and diagnosis. However, both acute and chronic GVHD remain serious barriers to successful allo-HCT and it is not clear that a major improvement has occurred in our ability to prevent or treat GVHD. Nevertheless, there is an increasing knowledge of the biology and clinical manifestations and the field is getting better organized. These advances will almost certainly lead to major progress in the near future. As the long list of new potential targets and respective drugs are developed, systems need to be developed for rapid testing of them in clinical practice. The current reality is that no single agent has yet to be approved by the US Food and Drug Administration for GVHD prevention or therapy. Although a primary goal of these efforts is to develop better therapies for GVHD, the ultimate goal is to develop treatments that lead to effective prevention or preemption of life-threatening and disabling GVHD manifestations while harnessing the desirable graft-versus-tumor effects.
Therapeutic challenges in acquired factor VIII deficiency
Authors: Collins Peter W. 
Published: October 2019

Abstract
Management of acquired hemophilia A is challenging and should be undertaken in close collaboration with a hemophilia center with expertise in the field. Treatment involves controlling and preventing bleeds and using immunosuppression to eradicate the inhibitor. Prompt diagnosis is important to allow early hemostatic treatment and to prevent nonessential invasive procedures. First-line hemostatic treatment should be with a bypassing agent. Recombinant activated factor VII and the activated prothrombin complex concentrate anti-inhibitor coagulant complex (Factor Eight Inhibitor Bypassing Activity, or FEIBA) but equally efficacious but both associated with thrombotic events when used in acquired hemophilia. Immunosuppression should be started as soon as a diagnosis has been confirmed. The combination of steroids and cyclophosphamide may induce more patients into remission than steroids alone. Current data do not suggest that rituximab results in better outcomes. Relapse is common (10%-20%) in the first 6 months after immunosuppression is stopped, and patients need to be followed up regularly to allow early diagnosis and treatment of relapse.
The gene therapy journey for hemophilia: are we there yet?
Authors: High Katherine A. 
Published: October 2019

AbstractSince the isolation and characterization of the genes for FVIII and FIX some 30 years ago, a longstanding goal of the field has been development of successful gene therapy for the hemophilias. In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno-associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of > 2 years. This review discusses obstacles that were overcome to reach this goal and the next steps in clinical investigation. Safety issues that will need to be addressed before more widespread use of this approach are discussed. Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed.
The molecular genetic makeup of acute lymphoblastic leukemia
Authors: Mullighan Charles G. 
Published: October 2019

Abstract
Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.
Updates in thrombosis in pediatrics: where are we after 20 years?
Authors: Chan Anthony K. C. , Monagle Paul 
Published: October 2019

AbstractThe incidence of venous thromboembolism (VTE) in the pediatric population is increasing. Technological advances in medicine and imaging techniques, improved awareness of the disease, and longer survival of life-threatening or chronic medical conditions all contribute to the increase in VTE rates. There is a paucity of data on management of VTE based on properly designed clinical trials, but there is significant advancement in the last 2 decades. This review summarizes the progress made in pediatric thrombosis, including epidemiological changes, advances in anticoagulant agents, and outcomes of VTE.