bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Insights into the Pathophysiology of Acquired Cytopenias
Authors: Young Neal S. , Abkowitz Janis L. , Luzzatto Lucio 
Published: October 2019

AbstractThis review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed.Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management.Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.
Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma
Authors: Macintyre Elizabeth , Willerford Dennis , Morris Stephan W. 
Published: October 2019

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL.In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly.In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues.In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
Gene Therapy 2000
Authors: Williams David A. , Nienhuis Arthur W. , Hawley Robert G. , Smith Franklin O. 
Published: October 2019

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.
Hematology Grants Workshop—2000
Authors: Todd Robert F. , Miller Donald M. , Silverstein Roy L. 
Published: October 2019

Abstract
This year the Hematology Grants Workshop, chaired by Dr. Robert Todd, includes a comprehensive listing of available NIH, VA, and non-federal grants applicable to fellows and junior faculty as well as to established investigators.
In Section II, Dr. Donald Miller discusses the essential principles of successful grant writing with a special emphasis on the young investigator. He highlights the best strategies to take and the common mistakes to avoid.
In Section III, Dr. Roy Silverstein outlines the structure of the current NIH Integrated Review Group (IRG) system and the study sections of the most relevance to hematology. He traces the path that a grant takes from review to funding including the way in which grants are reviewed at NIH Study Section Meetings and provides advice in the preparation of revised applications.
The incidence, natural history, biology, and treatment of transformed lymphomas
Authors: Bernstein Steven H. , Burack W. Richard 
Published: October 2019

AbstractTreatment of patients with transformed lymphoma presents a significant challenge to the practicing physician. Indeed, the transformation of follicular lymphoma to a more aggressive histology is inherent to the biology of this disease and is often associated with an aggressive clinical course, resulting in a poor prognosis. Recent population-based studies have better defined the incidence of this event, and recent laboratory studies have defined the molecular and immunological processes associated with transformation. These studies will be discussed in this review, as will the treatment options for these patients.
The Clinical Relevance of Response Variability to Antiplatelet Therapy
Authors: Cattaneo Marco 
Published: October 2019

Abstract
Interindividual variability in the pharmacological response to antiplatelet drugs has been reported in some studies. Suboptimal response to aspirin, as determined by specific tests (serum thromboxane B2), appears to be rare and in most cases is caused by poor compliance. In contrast, studies using specific tests to measure the pharmacological effect of clopidogrel showed a wide variability of responses, with a significant number of subjects (approximately one-third) who were very poor responders. Interindividual differences in the extent of metabolism of clopidogrel to its active metabolite is the most plausible mechanism for the observed interindividual variability in platelet inhibition. Tailored treatment based on laboratory monitoring of platelet function has been proposed as a solution to poor responsiveness to clopidogrel. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness before monitoring clopidogrel therapy can be recommended in clinical practice.
How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia?
Authors: Patel Jay P. , Levine Ross L. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and the majority of patients with AML die from relapsed disease. Although many studies over the past 4 decades have identified disease alleles in AML, recent genome-wide and candidate gene studies have identified additional recurrent somatic mutations in AML patients with biologic, clinical, and therapeutic importance. Herein we review our current understanding of the molecular pathogenesis of AML and discuss how mutational profiling can be used to refine prognostication in AML and to inform therapeutic approaches. We also review the current challenges in translating genomic studies to the clinical setting, which remains a significant challenge and an urgent priority.
Is there a role for “watch and wait” in follicular lymphoma in the rituximab era?
Authors: Kahl Brad 
Published: October 2019

AbstractThe paradigm of “watch and wait” for low-tumor-burden follicular lymphoma (LTB-FL) was established in an era when the treatment options were more limited. With the introduction of rituximab, it appears that the natural history of this incurable disease has changed. However, most of the contemporary treatment data have been generated in patients with high tumor burden, and it is unclear whether the improvements in outcome also apply to the LTB population. There are no published trials evaluating rituximab-chemotherapy combinations and just a few studies evaluating single-agent rituximab in this population. As a result, there are many unknowns in the management of LTB-FL. Would the application of rituximab-chemotherapy combination cure a fraction of patients? Would the application of rituximab-chemotherapy combination improve the overall survival of the population? Would treatment with single-agent rituximab improve the psychologic quality of life by avoiding a watch and wait interval or by delaying the time to first chemotherapy? This review, a mixture of data and opinion, will discuss goals of therapy for an LTB-FL patient, summarize existing data, and propose a management algorithm.
Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia
Authors: Wiestner Adrian 
Published: October 2019

AbstractChronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease “addicted to the host” and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.
Treatment-free remission in CML: who, how, and why?
Authors: Mahon Francois-Xavier 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.
HEMATOLOGIC EFFECTS OF SPLENECTOMY IN STILL-CHAUFFARD-FELTY SYNDROME
Authors: HIRSCHBOECK JOHN S. 
Published: October 2019

Abstract
Two cases of Still-Chauffard-Felty syndrome treated by splenectomy are presented. One case has survived five years with complete hematologic restitution and definite improvement in the arthritis. The second case expired six weeks after splenectomy. Autopsy revealed portal vein thrombosis (pylephlebitis). Both cases exhibited the blood manifestations associated with "hypersplenism." In both cases splenectomy resulted in a return of the peripheral blood picture to relative normality.
TREATMENT OF LIVER EXTRACT SENSITIVITY
Authors: SCHWARTZ STEVEN O. , LEGERE HELEN 
Published: October 2019

Abstract
Sensitivity reactions to the parenteral administration of liver extract are not uncommon. They were present in 68 of 396 patients (17 per cent) receiving liver therapy.
The symptoms of sensitivity to liver extract are those of any foreign protein reaction.
Various technics can be used to circumvent reactions and still maintain patients on adequate doses of liver extract.
These methods are:
A. Changing the "brand" or type of liver extract.
B. Reducing the dose of liver extract.
C. Desensitization with liver extract.
D. Utilizing a histamine-protein complex as an antigen to produce histamine antibodies.
The latter method was successful in 10 of 11 cases in which other methods had been without effect.
RUPTURE OF THE SPLEEN IN INFECTIOUS MONONUCLEOSIS
Authors: SMITH E. B. , CUSTER R. P. 
Published: October 2019

Abstract
1. Seven cases of ruptured spleen as a complication of infectious mononucleosis are described and reference made to the 3 cases previously recorded in the literature.
2. It proved possible to make an objective histologic diagnosis of infectious mononucleosis from well prepared sections of the spleens. The diagnosis was based on: (a) a blurred architectural pattern due chiefly to large numbers of atypical lymphocytes diffused throughout the pulp and clumped in the blood sinuses; (b) small, poorly defined follicles, usually without germinal centers, in less than usual numbers per unit area; (c) cellular "infiltrates," composed largely of normal and atypical lymphocytes, in the capsule and trabeculae, in the adventitia of small intratrabecular arteries, and in the subintimal zone of collecting venous sinuses and intratrabecular veins; (d) swelling of the lining or attached cells of the blood sinuses.
3. "Infiltration" of the capsule and trabeculae reached considerable proportions, occasionally to the point of complete dissolution of these structures, and served as a predisposing cause of rupture. The same changes were noted in intact spleens from fatal cases of infectious mononucleosis.
4. The spleen in infectious mononucleosis was 3 to 4 times normal size and ruptured during the third or fourth week of the disease.
5. The importance of trivial injury as the exciting cause of so-called "spontaneous" rupture of the spleen has been emphasized. It is recommended that extreme caution be employed during attempted palpation of the spleen in a suspected case of the disease. When the diagnosis is obvious, splenic palpation may well be omitted.
Hodgkin’s Disease
Authors: SHIMKIN MICHAEL B. 
Published: October 2019

Abstract
Mortality from Hodgkin’s disease in the United States during the period 1921 through 1951 was analyzed with respect to race, sex and age incidence and distribution. The findings were compared with those reported for leukemia.
The recorded death rate from Hodgkin’s disease rose from 6.9 in 1921 to 17.0 per million in 1951. During this period, the death rate from leukemia rose from 14 to 61 per million.
The death rate among males is higher than among females for both diseases; the male predominance is more marked in Hodgkin’s disease than in leukemia. The rate is higher among whites than non-whites for both diseases; the white predominance is more marked in leukemia than in Hodgkin’s disease. There is no peak in rate during childhood for Hodgkin’s disease as there is for leukemia, and the increase in rate with age is much less steep for Hodgkin’s disease than for leukemia.
The mean age at death of adults dying from Hodgkin’s disease and from leukemia increased by 3.5 and 8.0 years, respectively, between 1925 and 1950. The male-female sex ratio for Hodgkin’s disease decreased slightly, and increased slightly for leukemia between 1925 and 1950.
Hypoproaccelerinemia
Authors: LEWIS JESSICA H. , FERGUSON JOHN H. 
Published: October 2019

Abstract
This communication is concerned with the case of a 3-year old girl who had shown a moderately severe bleeding tendency since the age of 6 months. The cause of the bleeding could be clearly attributed to a marked deficiency in plasma proaccelerin and platelet accelerator factor. Abnormalities were also found in the clotting time, prothrombin consumption and Quick test. That this was probably familial in nature was suggested by moderately reduced plasma proaccelerin levels in the patient’s parents and in one sibling.*
Studies of Coagulation and Fibrinolysis by New Technic of Continuous Recording
Authors: VON KAULLA KURT N. , WEINER MURRAY 
Published: October 2019

Abstract
1. The Hartert instrument is a useful tool for recording continuously changes in a physical property of the clot during its formation and dissolution.
2. Alterations in fibrinogen content, platelets, and plasma clotting factors influence the pattern of the coagulogram. These patterns do not necessarily parallel the results of classical clotting time studies based on observation of the time necessary to form a visible clot. Clearly visible clots may not be sufficiently firm to be recorded by the coagulograph.
3. Coagulograph studies require careful handling of blood specimens to avoid artefacts of extrinsic origin.
4. The lysis of clots by different enzymes follows significantly different patterns which are not detectable by the standard methods for observing the dissolution of a clot.
Absorption Microspectroscopy of Bone Marrow Cells
Authors: DE CARVALHO SÉRGIO 
Published: October 2019

Abstract
Using a microspectrographic technic, reflecting optics and narrow bands of the continuum (5500, 4150 and 2650 Å), the author has obtained pictures of human and rat bone marrow cells in unfixed dry smears as well as in suspensions in vivo; erythroblasts showed different absorption patterns. Violet light microspectrography, specific for heme absorption, allowed us to demonstrate the presence of intranuclear heme granules through various stages of maturation of these cells. This confirmed previous and simultaneous results arrived at by cytochemical and other methods.
The presence of nucleic acids has been demonstrated in neutrophil granulations.
Megaloblastic Anemia of Pregnancy in Two Sisters
Authors: HOLLINGSWORTH JAMES W. , ADAMS FAE M. 
Published: October 2019

Abstract
1. Two sisters with megaloblastic anemia of pregnancy were reported.
2. Erythrocytes from the patients, both before and after therapy with folic acid, were tagged with radioactive sodium chromate and injected into normal subjects. The results of these studies were discussed.
Marrow Fibrosis in Myelodysplastic Syndromes - Its Significance in the Context of the WHO Classification of Disease and the International Prognostic Scoring System.
Authors: Buesche Guntram , Ganser Arnold , Wilkens Ludwig , Schlegelberger Brigitte , Hecker Hartmut , Georgii Axel , Kreipe Hans H. 
Published: October 2019

Abstract
Marrow fibrosis (MF) is rarely considered in myelodysplastic syndromes (MDS) although the frequency of this complication ranges from 10 to 50 % in the few reports on this issue, and there are no data on occurrence and significance of this complication in the context of the International Prognostic Scoring System (IPSS) and the World Health Organization (WHO) classification of disease. In a retrospective study, diagnostic bone marrow biopsies from a total of 936 patients with MDS were examined for MF and its relevance to the course of disease. Frequency of MF varied markedly between different types of MDS ranging from 3 % (RARS) to 37 % (MDS, therapy-related; WHO classification, P < 0.000005). Risk of MF furthermore correlated with multilineage dysplasia (P < 0.000005). However, there was no obvious correlation to the IPSS or to karyotype abnormalities. The survival time of patients was significantly reduced by about 50 % from 11 (RAEB-1/-2) - 55 (RARS, RCMD-RS) down to 6 (RAEB-1/-2) - 33 months (RARS, RCMD-RS) in median when MF was detected independently of the IPSS and the classification of disease (FAB, WHO; P = 0.0001). We conclude that MF is an unfavorable complication of MDS significantly shortening the survival time of patients independently of the IPSS and the classification of disease.