bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepcidin and Its Role in Regulating Systemic Iron Metabolism
Authors: Ganz Tomas 
Published: November 2006

AbstractMaintenance of stable extracellular iron concentrations requires the coordinate regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages and from storage in hepatocytes. Moreover, during fetal development, the iron requirements of the fetus must be matched by the transport of maternal iron across the placenta. Hepcidin is a 25–amino acid disulfide-rich peptide synthesized in the liver that acts as a systemic iron-regulatory hormone by regulating iron transport from iron-exporting tissues into plasma. Hepcidin inhibits the cellular efflux of iron by binding to, and inducing the degradation of, ferroportin, the sole iron exporter in iron-transporting cells. In turn, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Additionally, hepcidin synthesis is greatly increased during inflammation, trapping iron in macrophages, decreasing plasma iron concentrations and causing iron-restricted erythropoiesis characteristic of anemia of inflammation (anemia of chronic disease). Recent studies indicate that hepcidin deficiency underlies most known forms of hereditary hemochromatosis. This implies that, with the exception of very rare mutations that affect the hepcidin gene itself or modify ferroportin to make it less responsive to hepcidin, hemochromatosis genes encode molecules that regulate hepcidin synthesis. The central involvement of hepcidin in iron regulation and its pathologies should make the eventual hepcidin assay useful for the diagnosis of iron disorders and the monitoring of their treatments. The development of hepcidin agonists and antagonists may provide useful therapeutics for the treatment of iron disorders.
Therapy of Peripheral T/NK Neoplasms
Authors: Greer John P. 
Published: November 2006

AbstractThe mature T/natural killer (NK) lymphoma/leukemias represent 5–15% of all non-Hodgkin lymphoma. These diseases have a geographic variation, with more nodal disease in North America and Europe, including peripheral T cell lymphomas, unspecified, anaplastic large cell lymphoma, and angioimmunoblastic T cell lymphoma; and more extranodal disease in Asia due to Epstein-Barr virus–related nasal NK/T lymphoma and human T-cell leukemia virus (HTLV)-1–associated adult T cell leukemia/lymphoma. The prognosis in most peripheral T/NK neoplasms is poor, with 5-year survival less than 30%. Progress has been slow due to the rarity of the diseases, geographic variation, relative chemoresistance, and lack of randomized trials. There is no consensus about optimal therapy in T/NK neoplasms, and recommendations are based on anecdotal reports, small series, and phase II trials. In this review, topics include the question of CHOP as standard therapy, prognostic factors, disease-adapted therapy, novel approaches, monoclonal antibody therapy, and stem cell transplantation.
Bisphosphonate Complications Including Osteonecrosis of the Jaw
Authors: Mehrotra Bhoomi , Ruggiero Salvatore 
Published: November 2006

AbstractBisphosphonate therapy has been incorporated in the standard management of patients with multiple myeloma–related bony disease. Although their efficacy in reducing skeletal related events is important in the supportive management of the myeloma patient, post-marketing experience with this class of agents, particularly the more potent intravenous agents pamidronate and zoledronic acid, have raised cautionary notes regarding the potential side effects of these agents. The focus of this session is to review the risk factors, incidence, prevention strategies and management of bisphosphonate-related osteonecrosis of the jaw. In addition, pathophysiology, incidence and monitoring for renal dysfunction during chronic therapy with these agents are reviewed.
Viral Infections in Patients with Hematological Malignancies
Authors: Wade James C. 
Published: November 2006

AbstractViral infections are important causes of morbidity and mortality for patients with a hematological malignancy. However, the true incidence and consequences of viral infections for these patients who undergo conventional nontransplant therapy are poorly defined. The difference in incidence and outcome of viral infections among patient groups is wide, but dependent upon the intensity and duration of T-cell–mediated immune suppression. Infections caused by cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), respiratory syncytial virus (RSV), parainfluenza viruses and influenza viruses have been intensely studied, yet newly recognized aspects of these viral infections including late CMV infection; the emergence of new viral pathogens (human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus); the development of molecular diagnostic techniques, and the potential of new agents for viral prophylaxis (maribavir), or preemptive therapy (valganciclovir) form the basis of this review. Well-designed prospective studies are needed to better clarify the spectrum of these viral infections and develop effective prevention and treatment strategies. Yet the increased use of agents like alemtuzumab that induce profound T-cell depletion demands that we develop a better understanding of viral infections that occur in patients with hematological malignancy who receive nontransplant therapy.
Acquired Factor VIII Inhibitors: Pathophysiology and Treatment
Authors: Ma Alice D. , Carrizosa Daniel 
Published: November 2006

AbstractHemophilia A is classically caused by a congenital deficiency of factor VIII, but an acquired form due to inhibitors to factor VIII (FVIII) typically presents later in life. Patients who develop such acquired factor VIII inhibitors may present with catastrophic bleeding episodes, despite having no prior history of a bleeding disorder. Though the disorder is rare, it is known to cause significant morbidity and mortality. This review will focus on what is currently known about acquired hemophilia A, its pathogenesis, its associated etiologies, and its treatment.
Thrombosis and Cancer: The Role of Screening for Occult Cancer and Recognizing the Underlying Biological Mechanisms
Authors: Lee Agnes Y. Y. 
Published: November 2006

AbstractThe association between cancer and thrombosis is well recognized. What is not known, however, is the exact relationship between these two common medical conditions. Although the development of venous thromboembolism (VTE) in a patient with known cancer is the most common presentation, in some patients, VTE may precede the diagnosis of malignancy by many months. The variation in clinical presentation is likely due to the heterogeneous biology of different tumor types and also reflects the limitations of detection or available diagnostic methods. Accumulating evidence now suggests that critical oncogenic events may also trigger activation of the coagulation cascade, leading to a prothrombotic environment that not only manifests as venous thromboembolic disease but also promotes the growth and progression of the malignancy. This chapter will review the evidence for screening for occult malignancy in patients presenting with unprovoked or idiopathic thrombosis, briefly outline the known biological relationships between malignancy and thrombosis, and summarize the clinical data on the potential anticancer effects of low molecular weight heparins (LMWHs).
Vaccine-Enhanced Donor Lymphocyte Infusion (veDLI)
Authors: Roback John D. 
Published: November 2006

AbstractHematopoietic stem cell or bone marrow transplantation (HSCT/BMT) is curative in many cases of hemato-logical malignancy, but the post-transplant course is often complicated by delayed immune reconstitution that predisposes to opportunistic infections and disease recurrence. Furthermore, since HLA-matched donors cannot be found for almost half of all patients that would benefit from HSCT, donors mismatched at 2-3 HLA loci are increasingly being used, which is associated with elevated rates of opportunistic infections. Donor lymphocyte infusion (DLI) is a powerful and direct approach to improve post-transplant immune function. For example, DLI using enriched antiviral cytolytic effectors (CTLs) has been shown to reconstitute cellular immunity to cytomega-lovirus (CMV) and Epstein-Barr virus (EBV) and prevent viral disease following HSCT.1 However, because in vitro expansion and purification of CTLs is lengthy, labor-intensive, and costly, it is rarely used clinically to prevent and treat viral infections following HSCT. Active vaccination after allogeneic transplantation to stimulate in vivo expansion of donor and/or recipient CTLs has been proposed as an alternative method to rapidly reconstitute antiviral immunity, prevent viral disease, and reduce adverse sequelae of antiviral drugs.2 Fortunately, recent progress has been made in developing vaccines and methodologies that are both safe and effective when administered to immunocompromised HSCT recipients.
RhoH is important for positive thymocyte selection and T-cell receptor signaling
Authors: Dorn Tatjana , Kuhn Ursula , Bungartz Gerd , Stiller Sebastian , Bauer Martina , Ellwart Joachim , Peters Thorsten , Scharffetter-Kochanek Karin , Semmrich Monika , Laschinger Melanie , Holzmann Bernhard , Klinkert Wolfgang E. F. , Straten Per Thor , Køllgaard Tania , Sixt Michael , Brakebusch Cord 
Published: November 2006

Abstract
RhoH is a small GTPase expressed only in the hematopoietic system. With the use of mice with targeted disruption of the RhoH gene, we demonstrated that RhoH is crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Furthermore, the differentiation and expansion of DN3 and DN4 thymocytes in vitro were severely impaired. These defects corresponded to defective TCR signaling. Although RhoH is not required for TCR-induced activation of ZAP70 and ZAP70-mediated activation of p38, it is crucial for the tyrosine phosphorylation of LAT, PLCγ1, and Vav1 and for the activation of Erk and calcium influx. These data suggest that RhoH is important for pre–TCR and TCR signaling because it allows the efficient interaction of ZAP70 with the LAT signalosome, thus regulating thymocyte development.
Naive recirculating B cells mature simultaneously in the spleen and bone marrow
Authors: Cariappa Annaiah , Chase Catharine , Liu Haoyuan , Russell Paul , Pillai Shiv 
Published: November 2006

AbstractWe have recently demonstrated that IgDhi B cells can occupy an extravascular perisinusoidal niche in the bone marrow in addition to the well-established follicular niche in conventional secondary lymphoid organs. The spleen has long been considered to be the site at which newly formed B lymphocytes mature into IgDhi naive recirculating B cells, but the existence of mutant mice that have selectively lost mature B cells in the bone marrow prompted an examination of B-cell maturation at this latter site. Following a single pulse of BrdU in intact mice, sequential labeling of more mature B-cell populations in the bone marrow suggested ongoing maturation at this site. Further evidence for B-cell maturation in the bone marrow was obtained from analyses of transitional B cells in splenectomized lymphotoxin α-deficient mice that lack all secondary lymphoid organs. In these mice, antibody-secreting cells recognizing multivalent antigens were also observed in the bone marrow following an intravenous microbial challenge. These data suggest that newly formed B cells mature into IgDhi B cells simultaneously in the spleen and the bone marrow and establish in a stringent manner that humoral immune responses can be initiated in situ in the bone marrow.
Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications
Authors: Jost Philipp J. , Ruland Jürgen 
Published: November 2006

AbstractThe transcription factor NF-κB is a tightly regulated positive mediator of T- and B-cell development, proliferation, and survival. The controlled activity of NF-κB is required for the coordination of physiologic immune responses. However, constitutive NF-κB activation can promote continuous lymphocyte proliferation and survival and has recently been recognized as a critical pathogenetic factor in lymphoma. Various molecular events lead to deregulation of NF-κB signaling in Hodgkin disease and a variety of T- and B-cell non-Hodgkin lymphomas either upstream or downstream of the central IκB kinase. These alterations are prerequisites for lymphoma cell cycling and blockage of apoptosis. This review provides an overview of the NF-κB pathway and discusses the mechanisms of NF-κB deregulation in distinct lymphoma entities with defined aberrant pathways: Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue (MALT) lymphoma, primary effusion lymphoma (PEL), and adult T-cell lymphoma/leukemia (ATL). In addition, we summarize recent data that validates the NF-κB signaling pathway as an attractive therapeutic target in T- and B-cell malignancies.
A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells
Authors: Graf Claudine , Heidel Florian , Tenzer Stefan , Radsak Markus P. , Solem Fian K. , Britten Cedrik M. , Huber Christoph , Fischer Thomas , Wölfel Thomas 
Published: November 2006

AbstractThe FLT3 receptor tyrosine kinase is expressed in more than 90% of acute myelogeneous leukemias (AMLs), up to 30% of which carry an internal tandem duplication (ITD) within the FLT3 gene. Although varying duplication sites exist, most FLT3-ITDs affect a single protein domain. We analyzed the FLT3-ITD of an AML patient for encoding HLA class I–restricted immunogenic peptides. One of the tested peptides (YVDFREYEYY) induced in vitro autologous T-cell responses restricted by HLA-A*0101 that were also detectable ex vivo. These peptide-reactive T cells recognized targets transfected with the patient's FLT3-ITD, but not wild-type FLT3, and recognized the patient's AML cells. Our results demonstrate that AML leukemic blasts can in principle process and present immunogenic FLT3-ITD neoepitopes. Therefore, FLT3-ITD represents a potential candidate target antigen for the immunotherapy of AML.
Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used
Authors: Loh Yvonne , Oyama Yu , Statkute Laisvyde , Quigley Kathleen , Yaung Kimberly , Gonda Elizabeth , Barr Walter , Jovanovic Borko , Craig Robert , Stefoski Dusan , Cohen Bruce , Burt Richard K. 
Published: November 2006

AbstractPatients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)—a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.
Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myeloma
Authors: Alsayed Yazan , Ngo Hai , Runnels Judith , Leleu Xavier , Singha Ujjal K. , Pitsillides Costas M. , Spencer Joel A. , Kimlinger Teresa , Ghobrial Joanna M. , Jia Xiaoying , Lu Ganwei , Timm Michael , Kumar Ashok , Côté Daniel , Veilleux Israel , Hedin Karen E. , Roodman G. David , Witzig Thomas E. , Kung Andrew L. , Hideshima Teru , Anderson Kenneth C. , Lin Charles P. , Ghobrial Irene M. 
Published: November 2006

Abstract
The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1–dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.
Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28
Authors: Mirenda Vincenzo , Jarmin Sarah J. , David Rachel , Dyson Julian , Scott Diane , Gu Yan , Lechler Robert I. , Okkenhaug Klaus , Marelli-Berg Federica M. 
Published: November 2006

AbstractProductive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell–mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)–derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4–mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules.
Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany
Authors: Schafmayer Clemens , Hartleb Jürgen , Tepel Jürgen , Albers Stefan , Freitag Sandra , Völzke Henry , Buch Stephan , Seeger Markus , Timm Birgit , Kremer Bernd , Fölsch Ulrich R , Fändrich Fred , Krawczak Michael , Schreiber Stefan , Hampe Jochen 
Published: November 2006

Abstract

Background
Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany.

Methods
One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry.

Results
The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001).

Conclusion
The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m2 have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones.
Identification of Carcinogenic Agents and Primary Prevention of Cancer
Authors: TOMATIS LORENZO 
Published: November 2006

Abstract:
During the annual Ramazzini Days, the Mayor of Carpi confers the Ramazzini Award on scientists deemed by the Collegium Ramazzini to have made outstanding contributions to furthering the aims of Bernardino Ramazzini in safeguarding public health. Dr. Lorenzo Tomatis was the Ramazzini Award recipient in 2005, and the presentation of the award was a highlight of the Symposium. The Ramazzini Lecture given by Dr. Tomatis follows.
Efficacy with High-Dose Aripiprazole After Olanzapine-Related Metabolic Disturbances
Authors: Chavez Benjamin , Poveda Rene A 
Published: November 2006

Objective: To report a case in which a patient tolerated and responded to high-dose aripiprazole and lost weight after having been on olanzapine for several years; a secondary objective is to discuss the use of aripiprazole dosages at higher than those recommended in the product's labeling. Case Summary: A 57-year-old man with a 30 year history of schizophrenia had been taking olanzapine for 4 years, with the dosage titrated to 20 mg/day, to control the psychosis. After he had gained significant weight with olanzapine (the highest was 102.7 kg), his treatment was switched to aripiprazole. The patient required a high dose of aripiprazole (60 mg/day) to achieve full control of the psychiatric symptoms, and during aripiprazole therapy, he lost the weight he had gained while on olanzapine, weighing 85.9 kg within 7 months after the therapy switch. Discussion: Dosages of atypical antipsychotics higher than those recommended by the Food and Drug Administration are often used in clinical practice for refractory patients, despite the lack of evidence. The literature available on this subject is limited to small, double-blind trials; open-label trials; and case reports. Although certain patients may benefit from higher doses of atypical antipsychotics, the lack of evidence limits their use. Conclusions: High-dose aripiprazole (60 mg/day) was well tolerated and controlled this patient's symptoms effectively. In addition, he lost weight that was gained while being treated with olanzapine. High-dose aripiprazole may be beneficial and safe in refractory patients; however, large, double-blind, randomized clinical trials are needed.