bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Myeloid Leukemia
Authors: Melo Junia V. , Hughes Timothy P. , Apperley Jane F. 
Published: November 2003

AbstractChronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.
Biology and Treatment of Chronic Lymphocytic Leukemia
Authors: Keating Michael J. , Chiorazzi Nicholas , Messmer Bradley , Damle Rajendra N. , Allen Steven L. , Rai Kanti R. , Ferrarini Manlio , Kipps Thomas J. 
Published: November 2003

AbstractMajor advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process.Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored.Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed.In Section III, Dr. Michael Keating examines the question “Do we have the tools to cure CLL?” and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance.The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.
Hodgkin’s Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease
Authors: Diehl Volker , Stein Harald , Hummel Michael , Zollinger Raphael , Connors Joseph M. 
Published: November 2003

Abstract
Hodgkin’s lymphomas belong to the most curable tumor diseases in adults. About 80% of patients in all anatomical stages and of all histological subtypes can be cured with modern treatment strategies. In spite of the great clinical progress, the pathogenesis of this peculiar lymphoproliferative entity has not been elucidated completely up until now.
In Section I Drs. Stein, Hummel, and Zollinger describe the different pro-proliferative and antiapoptotic pathways and molecules involved in the transformation of the germinal center B-lymphocyte to the malignant Hodgkin-Reed-Sternberg cell. They use a comprehensive gene expression profiling (Affymetrix gene chip U133A) on B- and T-Hodgkin cell lines and state that the cell of origin is not the dominant determinant of the Hodgkin cell phenotype, but the transforming event. H-RS cells lack specific functional markers (B-T-cell receptors) and physiologically should undergo apoptosis. Why they do not is unclear and a matter of intensive ongoing research.
In Section II Dr. Diehl summarizes the commonly used primary treatment strategies adapted to prognostic strata in early, intermediate and advanced anatomical stages using increasing intensities of chemotherapy (two, four, eight courses of chemotherapy such as ABVD) and additive radiation with decreased doses and field size. ABVD is without doubt the gold standard for early and intermediate stages, but its role as the standard regimen for advanced stages is challenged by recent data with time- and dose-intensified regimens such as the escalated BEACOPP, demonstrating superiority over COPP/ABVD (equivalent to ABVD) for FFTF and OS in all risk strata according to the International Prognostic Score.
In Section III, Dr. Connors states that fortunately there is a considerably decreased need for salvage strategies in Hodgkin’s lymphomas since primary treatment results in a more than 80% tumor control. Nevertheless, a significant number of patients experience either a tumor refractory to therapy or an early or late relapse. Therefore, one of the continuing challenges in the care for Hodgkin’s lymphomas today is to find effective modes for a second tumor control. High-dose chemotherapy followed by autologous stem cell support has proved to be the treatment of choice when disseminated tumors recur after primary chemo- and or radiotherapy. Nodal relapses respond well to local radiation when they recur outfield of primary radiation without B-symptoms and in stages I–II at relapse. Allogeneic stem cell support needs further intensive evaluation in controlled studies to become an established alternative.
Stem Cell Mobilization
Authors: Cottler-Fox Michele H. , Lapidot Tsvee , Petit Isabelle , Kollet Orit , DiPersio John F. , Link Dan , Devine Steven 
Published: November 2003

Abstract
Successful blood and marrow transplant (BMT), both autologous and allogeneic, requires the infusion of a sufficient number of hematopoietic progenitor/stem cells (HPCs) capable of homing to the marrow cavity and regenerating a full array of hematopoietic cell lineages in a timely fashion. At present, the most commonly used surrogate marker for HPCs is the cell surface marker CD34, identified in the clinical laboratory by flow cytometry. Clinical studies have shown that infusion of at least 2 × 106 CD34+ cells/kg recipient body weight results in reliable engraftment as measured by recovery of adequate neutrophil and platelet counts approximately 14 days after transplant. Recruitment of HPCs from the marrow into the blood is termed mobilization, or, more commonly, stem cell mobilization.
In Section I, Dr. Tsvee Lapidot and colleagues review the wide range of factors influencing stem cell mobilization. Our current understanding focuses on chemokines, proteolytic enzymes, adhesion molecules, cytokines and stromal cell-stem cell interactions. On the basis of this understanding, new approaches to mobilization have been designed and are now starting to undergo clinical testing.
In Section II, Dr. Michele Cottler-Fox describes factors predicting the ability to mobilize the older patient with myeloma. In addition, clinical approaches to improving collection by individualizing the timing of apheresis and adjusting the volume of blood processed to achieve a desired product are discussed. Key to this process is the daily enumeration of blood CD34+ cells. Newer methods of enumerating and mobilizing autologous blood HPCs are discussed.
In Section III, Dr. John DiPersio and colleagues provide data on clinical results of mobilizing allogeneic donors with G-CSF, GM-CSF and the combination of both as relates to the number and type of cells collected by apheresis. Newer methods of stem cell mobilization as well as the relationship of graft composition on immune reconstitution and GVHD are discussed.
Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome
Authors: Warkentin Theodore E. , Aird William C. , Rand Jacob H. 
Published: November 2003

AbstractAcquired abnormalities in platelets, endothelium, and their interaction occur in sepsis, immune heparin-induced thrombocytopenia (HIT), and the antiphospholipid syndrome. Although of distinct pathogeneses, these three disorders have several clinical features in common, including thrombocytopenia and the potential for life- and limb-threatening thrombotic events, ranging from microvascular (sepsis &gt; antiphospholipid &gt; HIT) to macrovascular (HIT &gt; antiphospholipid &gt; sepsis) thrombosis, both venous and arterial.In Section I, Dr. William Aird reviews basic aspects of endothelial-platelet interactions as a springboard to considering the common problem of thrombocytopenia (and its mechanism) in sepsis. The relationship between thrombocytopenia and other aspects of the host response in sepsis, including activation of coagulation/inflammation pathways and the development of organ dysfunction, is discussed. Practical issues of platelet count triggers and targeted use of activated protein C concentrates are reviewed.In Section II, Dr. Theodore Warkentin describes HIT as a clinicopathologic syndrome, i.e., the diagnosis should be based on the concurrence of an appropriate clinical picture together with detection of platelet-activating and/or platelet factor 4-dependent antibodies (usually in high levels). HIT is a profound prothrombotic state (odds ratio for thrombosis, 20–40), and the risk for thrombosis persists for a time even when heparin is stopped. Thus, pharmacologic control of thrombin (or its generation), and postponing oral anticoagulation pending substantial resolution of thrombocytopenia, is appropriate. Indeed, coumarin-associated protein C depletion during uncontrolled thrombin generation of HIT can explain limb loss (coumarin-associated venous limb gangrene) or skin necrosis syndromes in some patients.In Section III, Dr. Jacob Rand presents the most recent concepts on the mechanisms of thrombosis in the antiphospholipid syndrome, and focuses on the role of β2-glycoprotein I as a major antigenic target in this condition. Diagnosis of the syndrome is often complicated because the clinical laboratory tests to identify this condition have been empirically derived. Dr. Rand addresses the practical aspects of current testing for the syndrome and current recommendations for treating patients with thrombosis and with spontaneous pregnancy losses.
Hematology Grants Workshop
Authors: Poncz Mortimer , Iannone Robert , Werner Ellen M. 
Published: November 2003

Abstract
Uppermost among the many concerns of young researchers is acquiring funding for beginning a career as a clinician-scientist. This chapter is targeted specifically at those individuals considering an academic physician-scientist career and those on the verge of becoming independent researchers.
In Section I, Drs. Poncz and Iannone discuss the Mentored Career Development Award (K08). They summarize the application process, highlighting the critical components of a successful application and what the review process entails.
In Section II, Dr. Werner discusses what applicants need to know about the NIH Institutes’ program, review, and grants management function; the different NIH staff whom applicants should contact during the various stages of the grants process; and the important sections and key phrases in NIH Program Announcements for career development awards.
Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice
Authors: Zhao Bing-Qiao , Ikeda Yasuhiko , Ihara Hayato , Urano Tetsumei , Fan WenYing , Mikawa Sumiko , Suzuki Yasuhiro , Kondo Kazunao , Sato Kohji , Nagai Nobuo , Umemura Kazuo 
Published: November 2003

Abstract
Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice but not in tissue plasminogen activator (tPA)–deficient knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans.
Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis
Authors: Klein John R. , Wang Heuy-Ching 
Published: November 2003

SUMMARYImmunofluorescent staining of thyroid tissues was done using monoclonal antibodies to dendritic cell (DC), lymphocyte, macrophage and granulocyte markers. Despite the presence of occasional CD11c+ cells,CD11b+ cells, morphologically characteristic of DCs, were abundant in thyroid of normal mice, at a density of ∼2.0 cells per thyroid follicle, and were &gt;tenfold more frequent than CD11c+ cells. Thyroid tissues were non-reactive with antibodies to F4/80, CD8α, CD40,CD80, Gr-1, CD3, or CD19, indicating that the CD11b+ cells were not macrophages, activated DCs, granulocytes, plasmacytoid DCs, T cells or B cells. Following systemic immune activation, DCs in secondary lymphoid tissues but not in the thyroid, upregulated CD80 expression. Using radiation chimeras made from bone marrow from enhanced green fluorescent protein (EGFP)transgenic mice, EGFP+ DC-like cells were present in the thyroid from 1–20 weeks after bone marrow transfer, but were rare in the kidney and liver, although EGFP+ cells were present in secondary lymphoid tissues. Additionally, DCs generated from EGFP+ bone marrow cells localized in the thyroid of EGFP– mice following adoptive transfer. Double staining of thyroid tissue sections with antibodies to the thyroid stimulating hormone (TSH)-β molecule and to CD11b revealed co-expression of TSHβ and CD11b among intrathyroidal DCs. Moreover,RT-PCR analyses indicated expression of the TSHβ gene in thyroid tissues. These findings define a novel bone marrow-derived hematopoietic cell population that resides in the thyroid of normal mice, which may have a unique role in the microregulation of thyroid physiology and homeostasis.
Physiological modulation of iron metabolism in rainbow trout(Oncorhynchus mykiss) fed low and high iron diets
Authors: Carriquiriborde P. , Handy R. D. , Davies S. J. 
Published: November 2003

SUMMARYIron (Fe) is an essential element, but Fe metabolism is poorly described in fish and the role of ferrireductase and transferrin in iron regulation by teleosts is unknown. The aim of the present study was to provide an overview of the strategy for Fe handling in rainbow trout, Oncorhynchus mykiss. Fish were fed Fe-deficient, normal and high-Fe diets (33, 175,1975 mg Fe kg-1 food, respectively) for 8 weeks. Diets were chosen so that no changes in growth, food conversion ratio, haematology, or significant oxidative stress (TBARS) were observed. Elevation of dietary Fe caused Fe accumulation particularly in the stomach, intestine, liver and blood. The increase in total serum Fe from 10 to 49 μmol l-1over 8 weeks was associated with elevated total Fe binding capacity and decreased unsaturated Fe binding capacity, so that in fish fed a high-Fe diet transferrin saturation increased from 15% at the start of the experiment to 37%. Fish on the high-Fe diet increased Fe accumulation in the liver, which was correlated with elevation of hepatic ferrireductase activity and serum transferrin saturation. Conversely, fish on the low-Fe diet did not show tissue Fe depletion compared with normal diet controls and did not change Fe binding to serum transferrin. Instead, these fish doubled intestinal ferrireductase activity which may have contributed to the maintenance of tissue Fe status. The absence of clear treatment-dependent changes in branchial Fe accumulation and ferrireductase activity indicated that the gills do not have a major role in Fe metabolism. Some transient changes in Cu, Zn and Mn status of tissues occurred.
Development of ultrasound detection in American shad (Alosa sapidissima)
Authors: Higgs D. M. , Plachta D. T. T. , Rollo A. K. , Singheiser M. , Hastings M. C. , Popper A. N. 
Published: November 2003

SUMMARYIt has recently been shown that a few fish species, including American shad(Alosa sapidissima; Clupeiformes), are able to detect sound up to 180 kHz, an ability not found in most other fishes. Initially, it was proposed that ultrasound detection in shad involves the auditory bullae, swim bladder extensions found in all members of the Clupeiformes. However, while all clupeiformes have bullae, not all can detect ultrasound. Thus, the bullae alone are not sufficient to explain ultrasound detection. In this study, we used a developmental approach to determine when ultrasound detection begins and how the ability to detect ultrasound changes with ontogeny in American shad. We then compared changes in auditory function with morphological development to identify structures that are potentially responsible for ultrasound detection. We found that the auditory bullae and all three auditory end organs are present well before fish show ultrasound detection behaviourally and we suggest that an additional specialization in the utricle(one of the auditory end organs) forms coincident with the onset of ultrasound detection. We further show that this utricular specialization is found in two clupeiform species that can detect ultrasound but not in two clupeiform species not capable of ultrasound detection. Thus, it appears that ultrasound-detecting clupeiformes have undergone structural modification of the utricle that allows detection of ultrasonic stimulation.
Bewegungsalgorithmen für zweibeinige Roboter ohne Oberkörper (Path Planning Algorithms for Bipedal Robots without a Trunk)
Authors: Albert Amos , Gerth Wilfried 
Published: November 2003

Abstract
Dieser Artikel stellt neue Algorithmen zur Bahnplanung zweibeiniger Roboter vor. Hierbei dienen die Beintrajektorien sowohl der Fortbewegung als auch der Stabilität. Es gelingt der Brückenschlag zwischen dem Konzept des Inversen Pendels (IPM) und den Verfahren auf Basis eines verallgemeinerten dynamischen Modells. Simulationen und Messungen der Fußreaktionskräfte während des Laufvorganges des realen Roboters BARt-UH verifizieren die Eignung der vorgestellten Verfahren.
Interaktionsmodelle in der Spezifikation: Von der Datenzentrierung zur Ablauforientierung (Interaction models in the requirements specification: From data centric to flow centric models)
Authors: Schlegel Thomas , Burst Alexander , Beger Dorit 
Published: November 2003

Zusammenfassung
In den frühen Projektphasen der Anwendungsentwicklung steht eine Vielzahl von Informationen von Kunden, Benutzern und Anwendungsdomänen zur Verfügung. Wird dieses Wissen mit Hilfe eines deskriptiven, interakions- und ablauforientierten Modells sedimentiert, kann es zur Generierung von UI-Prototypen und Entwicklungsdokumenten genutzt werden. Hier soll eine Modellierungsmethode aufgezeigt werden, mit der es möglich ist, Wissen aus der Analyse- und Spezifikationsphase in ein Interaktionsmodell einzubringen und so über die Projektlaufzeit zu konservieren. Die Eignung für eine iterative und inkrementelle Vorgehensweise und die Möglichkeit zur Generierung von Oberflächenprototypen soll zudem eine stärkere Partizipation von Kunden und Benutzern am Entwicklungsprozess ermöglichen.
Anpassungsumgebung für komponentenbasierte Software: Kooperativ und lernförderlich (A cooperative and easy-to-learn Tailoring Environment for component-based architectures)
Authors: Won Markus , Wulf Volker 
Published: November 2003

Zusammenfassung
Der Aufsatz beschreibt eine komponentenbasierte Anpassungsumgebung, die Adaptionen der Software zur Laufzeit auf verschiedenen Komplexitätsebenen erlaubt. Die Anpassungsumgebung unterstützt auch den Austausch von angepassten Artefakten zwischen Nutzern. Erläutert wird die Anpassungsumgebung am Beispiel eines Suchwerkzeugs einer Groupware, das Benutzer entsprechend ihren Anforderungen in verschiedener Weise modifizieren können. Nutzungsprobleme ergaben sich bei der Einführung der Anpassungsumgebung in eine Organisation der öffentlichen Verwaltung sowohl bezüglich der eigenständigen Komposition von Suchwerkzeugen als auch bei von Kollegen übernommenen Suchwerkzeugen. Basierend auf dieser Problemanalyse wurden verschiedene Konzepte entwickelt, die sowohl das individuelle als auch das kooperative Erlernen der neuen Anpassungsmöglichkeiten erleichtern. Im Bereich des individuellen Lernens wird das endbenutzerorientierte Anpassen vor allem durch semi-automatische Überprüfung der Integrität der Komposition unterstützt. Auf der kooperativen Ebene helfen Explorationsmöglichkeiten und Annotationen. Beide Konzepte unterstützen die Kommunikation zwischen Benutzern über die Bedeutung von Kompositionen.