bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron?
Authors: Leitch Heather A. , Vickars Linda M. 
Published: December 2009

AbstractThe myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of transformation to acute myeloid leukemia (AML). Although new treatments are available, a mainstay in MDS remains supportive care, which aims to minimize the impact of cytopenias and transfusion of blood products. Red blood cell (RBC) transfusions place patients at risk of iron overload (IOL). In beta-thalassemia major (BTM), IOL from chronic RBC transfusions inevitably leads to organ dysfunction and death. With iron chelation therapy (ICT), survival in BTM improved from the second decade to near normal and correlated with ICT compliance. Effects of ICT in BTM include reversal of cardiac arrhythmias, improvement in left ventricular ejection fraction, arrest of hepatic fibrosis, and reduction of glucose intolerance.It is not clear whether these specific outcomes are applicable to MDS. Although retrospective, recent studies in MDS suggest an adverse effect of transfusion dependence and IOL on survival and AML transformation, and that lowering iron minimizes this impact. These data raise important points that warrant further study. ICT is potentially toxic and cumbersome, is costly, and in MDS patients should be initiated only after weighing potential risks against benefits until further data are available to better justify its use. Since most MDS patients eventually require RBC transfusions, the public health implications both of transfusion dependence and ICT in MDS are considerable. This paper summarizes the impact of cytopenias in MDS and treatment approaches to minimize their impact, with a focus on RBC transfusions and their complications, particularly with respect to iron overload.
Overview of gene therapy clinical progress including cancer treatment with gene-modified T cells
Authors: Brenner Malcolm K. , Okur Fatma V. 
Published: December 2009

Abstract
It is now twenty years since the first legal gene transfer studies were approved, and there has been considerable disappointment in the slow rate of progress that followed the initial studies. Gradually, however, as the limitations of available vectors are acknowledged and overcome, and with advances in our understanding of the molecular and cell biology of genetic diseases and of cancer, unequivocal successes are now being reported. In this paper we describe the remaining major roadblocks to successful gene therapy and outline approaches to overcome them. We also illustrate how genetically modified immune system cells are already being used for the effective treatment of hematological and other malignancies, and how these approaches are being modified so that they can be effective in treating a broader range of malignancies.
Ten years of gene therapy for primary immune deficiencies
Authors: Aiuti Alessandro , Roncarolo Maria Grazia 
Published: December 2009

Abstract
Gene therapy with hematopoietic stem cells (HSC) is an attractive therapeutic strategy for several forms of primary immunodeficiencies. Current approaches are based on ex vivo gene transfer of the therapeutic gene into autologous HSC by vector-mediated gene transfer. In the past decade, substantial progress has been achieved in the treatment of severe combined immundeficiencies (SCID)-X1, adenosine deaminase (ADA)-deficient SCID, and chronic granulomatous disease (CGD). Results of the SCID gene therapy trials have shown long-term restoration of immune competence and clinical benefit in over 30 patients. The inclusion of reduced-dose conditioning in the ADA-SCID has allowed the engraftment of multipotent gene-corrected HSC at substantial level. In the CGD trial significant engraftment and transgene expression were observed, but the therapeutic effect was transient. The occurrence of adverse events related to insertional mutagenesis in the SCID-X1 and CGD trial has highlighted the limitations of current retroviral vector technology. For future applications the risk-benefit evaluation should include the type of vector employed, the disease background and the nature of the transgene. The use of self-inactivating lentiviral vectors will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events. Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome.
Application of semiconductor and metal nanostructures in biology and medicine
Authors: Walkey Carl , Sykes Edward A. , Chan Warren C. W. 
Published: December 2009

AbstractAdvances in nanotechnology research have led to the creation of new generation of contrast agents, therapeutics, and delivery systems. These applications are expected to significantly improve the diagnosis and treatment of a variety of diseases. Two nanotechnologies—semiconductor and metallic nanostructures—are the most advanced in this young field and have been extensively investigated for clinical use. These nanostructures are currently the “model” for the developments of many novel nanostructures. This review describes their chemical design, tunable properties, and utility in medicine. Furthermore, we will describe the current understanding of their toxicity, which could be barriers to their use for human.
Dendrimer-based nanoparticles for cancer therapy
Authors: Baker James R. 
Published: December 2009

AbstractRecent work has suggested that nanoparticles in the form of dendrimers may be a keystone in the future of therapeutics. The field of oncology could soon be revolutionized by novel strategies for diagnosis and therapy employing dendrimer-based nanotherapeutics. Several aspects of cancer therapy would be involved. Diagnosis using imaging techniques such as MRI will be improved by the incorporation of dendrimers as advanced contrast agents. This might involve novel contrast agents targeted specifically to cancer cells. Dendrimers can also be being applied to a variety of cancer therapies to improve their safety and efficacy. A strategy, somewhat akin to the “Trojan horse,” involves targeting anti-metabolite drugs via vitamins or hormones that tumors need for growth. Further applications of dendrimers in photodynamic therapy, boron neutron capture therapy, and gene therapy for cancer are being examined. This presentation will cover the fundamentals of research utilizing dendrimers for cancer diagnosis and therapy. An evaluation of this new technologies will detail what advantage dendrimer based therapeutics might have over conventional cancer drugs.
Drug-induced immune hemolytic anemia
Authors: Garratty George 
Published: December 2009

AbstractDrug-induced immune hemolytic anemia (DIIHA) is rare, and a specialized laboratory is often required to provide the optimal serological tests to confirm the diagnosis. The most common drugs associated with DIIHA and the hypotheses for the mechanisms thought to be involved have changed during the last few decades. The drugs most frequently associated with DIIHA at this time are cefotetan, ceftriaxone, and piperacillin. DIIHA is attributed most commonly to drug-dependent antibodies that can only be detected in the presence of drug (eg, cephalosporin antibodies). DIIHA can also be associated with drug-independent antibodies; such antibodies do not need drug to be present to obtain in vitro reactions (eg, fludarabine). In these latter cases, the drug affects the immune system, causing production of red cell (RBC) autoantibodies; the clinical and laboratory findings are identical to autoimmune hemolytic anemia (AIHA), other than the remission associated with discontinuing the drug. Some of the mechanisms involved in DIIHA are controversial. The most acceptable one involves drugs, like penicillin, that covalently bind to proteins (eg, RBC membrane proteins); RBCs become coated with drug in vivo and, a drug antibody (usually IgG) attaches to the drug-coated RBCs that are subsequently cleared by macrophages. The most controversial is the so-called immune complex mechanism, which has been revised to suggest that most drugs are capable of binding to RBC membrane proteins, but not covalently like penicillins. The combined membrane plus drug can create an immunogen; the antibodies formed can be IgM or IgG and often activate complement, leading to acute intravascular lysis and sometimes renal failure; fatalities are more common in this group. It is still unknown why and how some drugs induce RBC autoantibodies, sometimes causing AIHA.
Immune hemolytic anemia—selected topics
Authors: Hoffman Philip C. 
Published: December 2009

Abstract
Autoimmune hemolytic anemia (AIHA) is most often idiopathic. However, in recent years, AIHA has been noted with increased incidence in patients receiving purine nucleoside analogues for hematologic malignancies; it has also been described as a complication of blood transfusion in patients who have also had alloimmunization. As the technology of hematopoietic stem cell transplantation has become more widespread, immune hemolysis in the recipients of ABO-mismatched products has become better recognized. The syndrome is caused by passenger lymphocytes transferred from the donor and, although transient, can be quite severe. A similar syndrome has been observed in recipients of solid organ transplants when there is ABO-incompatibility between donor and recipient.
Venous thromboembolism is a little-recognized, though likely common, complication of AIHA, and may in some instances be related to coexistent antiphospholipid antibodies. While AIHA is a well-documented complication of malignant lymphoproliferative disorders, lymphoproliferative disorders may also paradoxically appear as a consequence of AIHA.
A number of newer options are available for treatment of AIHA in patients refractory to corticosteroids and splenectomy. Newer immunosuppressives such as mycophenolate mofetil may have a role in such cases. Considerable experience has been accumulating in the last few years with monoclonal antibody therapy, mainly rituximab, in difficult AIHA cases; it appears to be a safe and effective option.
Malaria, erythrocytic infection, and anemia
Authors: Haldar Kasturi , Mohandas Narla 
Published: December 2009

AbstractMalaria is a major world health problem. It results from infection of parasites belonging to the genus Plasmodium. Plasmodium falciparum and Plasmodium vivax cause the major human malarias, with P falciparum being the more virulent. During their blood stages of infection, both P falciparum and P vivax induce anemia. Severe malarial anemia caused by P falciparum is responsible for approximately a third of the deaths associated with disease. Malarial anemia appears to be multi-factorial. It involves increased removal of circulating erythrocytes as well as decreased production of erythrocytes in the bone marrow. The molecular mechanisms underlying malarial anemia are largely unknown. Over the last five years, malaria parasite ligands have been investigated for their remodeling of erythrocytes and possible roles in destruction of mature erythrocytes. Polymorphisms in cytokines have been associated with susceptibility to severe malarial anemia: these cytokines and malaria “toxins” likely function by perturbing erythropoiesis. Finally a number of co-infections increase susceptibility to malarial anemia, likely because they exacerbate inflammation caused by malaria. Because of the complexities involved, the study of severe malarial anemia may need a “systems approach” to yield comprehensive understanding of defects in both erythropoiesis and immunity associated with disease. New and emerging tools such as (i) mathematical modeling of the dynamics of host control of malarial infection, (ii) ex vivo perfusion of human spleen to measure both infected and uninfected erythrocyte retention, and (iii) in vitro development of erythroid progenitors to dissect responsiveness to cytokine imbalance or malaria toxins, may be especially useful to develop integrated mechanistic insights and therapies to control this major and fatal disease pathology.
Factor XI deficiency—resolving the enigma?
Authors: Bolton-Maggs Paula H. B. 
Published: December 2009

Abstract
The management of factor XI deficiency is not straightforward for three reasons: firstly, the role of this factor in the coagulation pathway is not clearly understood; secondly, the bleeding tendency, although mild, is unpredictable and does not clearly relate to the factor XI level; and thirdly, all treatment products, although available, have some potentially serious side effects. These factors (or enigmas) contribute to the variable management of patients with this coagulation factor deficiency, but recent research is helping to clarify some of these areas.
Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells
Authors: Colisson Renaud , Barblu Lucie , Gras Christophe , Raynaud Françoise , Hadj-Slimane Reda , Pique Claudine , Hermine Olivier , Lepelletier Yves , Herbeuval Jean-Philippe 
Published: December 2009

Abstract
A recent report demonstrated that free human T-cell leukemia virus 1 (HTLV-1) could infect plasmacytoid dendritic cells (pDCs). The major role of pDCs is to secrete massive levels of interferon-α (IFN-α) upon virus exposure; however, the induction of IFN-α by HTLV-1 remains unknown. We demonstrate here that cell-free HTLV-1 generated a pDC innate immune response by producing massive levels of IFN-α that were inhibited by anti–HTLV-1 antibodies. HTLV-1 induced costimulatory molecules and rapid expression of the apoptotic ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Furthermore, HTLV-1 stimulated pDC-induced apoptosis of CD4+ T cells expressing DR5, transforming pDCs into IFN-producing killer pDCs. We also observed that an endosomal acidification inhibitor and a Toll-like receptor-7 (TLR7)–specific blocker drastically inhibited pDC response to HTLV-1. Three-dimensional microscopy analysis revealed that unstimulated pDCs were “dormant” IFN-producing killer pDCs with high levels of intracellular TRAIL that could be rapidly mobilized to the surface in response to TLR7 activation. Inhibition of viral degradation in endosomes by chloroquine maintained viral integrity, allowing virus detection by 3-dimensional microscopy. We demonstrate that pDCs respond to cell-free HTLV-1 by producing high levels of IFN-α and by mobilizing TRAIL on cell surface after TLR7 triggering. This is the first demonstration of an innate immune response induced by free HTLV-1.
Emergence of BCR-ABL–specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term imatinib mesylate treatment
Authors: Riva Giovanni , Luppi Mario , Barozzi Patrizia , Quadrelli Chiara , Basso Sabrina , Vallerini Daniela , Zanetti Eleonora , Morselli Monica , Forghieri Fabio , Maccaferri Monica , Volzone Francesco , Del Giovane Cinzia , D'Amico Roberto , Locatelli Franco , Torelli Giuseppe , Comoli Patrizia , Potenza Leonardo 
Published: December 2009

Abstract
Imatinib mesylate has been demonstrated to allow the emergence of T cells directed against chronic myeloid leukemia cells. A total of 10 Philadelphia chromosome–positive acute lymphoblastic leukemia patients receiving high-dose imatinib mesylate maintenance underwent long-term immunological monitoring (range, 2-65 months) of p190BCR-ABL–specific T cells in the bone marrow and peripheral blood. p190BCR-ABL–specific T lymphocytes were detected in all patients, more frequently in bone marrow than in peripheral blood samples (67% vs 25%, P < .01) and resulted significantly associated with lower minimal residual disease values (P < .001), whereas absent at leukemia relapse. Specific T cells were mainly effector memory CD8+ and CD4+ T cells, producing interferon-γ, tumor necrosis factor-α, and interleukin-2 (median percentage of positive cells: 3.34, 3.04, and 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL–positive leukemia blasts also were detectable. Whether these autologous p190BCR-ABL–specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo, and exploited for immunotherapy remains to be addressed.
Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1: unexpected implications for collagen binding by platelet receptor GPVI
Authors: Brondijk T. Harma C. , de Ruiter Talitha , Ballering Joost , Wienk Hans , Lebbink Robert Jan , van Ingen Hugo , Boelens Rolf , Farndale Richard W. , Meyaard Linde , Huizinga Eric G. 
Published: December 2009

AbstractLeukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), one of the most widely spread immune receptors, attenuates immune cell activation when bound to specific sites in collagen. The collagen-binding domain of LAIR-1 is homologous to that of glycoprotein VI (GPVI), a collagen receptor crucial for platelet activation. Because LAIR-1 and GPVI also display overlapping collagen-binding specificities, a common structural basis for collagen recognition would appear likely. Therefore, it is crucial to gain insight into the molecular interaction of both receptors with their ligand to prevent unwanted cross-reactions during therapeutic intervention. We determined the crystal structure of LAIR-1 and mapped its collagen-binding site by nuclear magnetic resonance (NMR) titrations and mutagenesis. Our data identify R59, E61, and W109 as key residues for collagen interaction. These residues are strictly conserved in LAIR-1 and GPVI alike; however, they are located outside the previously proposed GPVI collagen-binding site. Our data provide evidence for an unanticipated mechanism of collagen recognition common to LAIR-1 and GPVI. This fundamental insight will contribute to the exploration of specific means of intervention in collagen-induced signaling in immunity and hemostasis.
Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development
Authors: Anderson Keith R , White Peter , Kaestner Klaus H , Sussel Lori 
Published: December 2009

AbstractBackgroundThe homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin-expressing cells. Additional studies have suggested that Nkx2.2 functions both as a transcriptional repressor and activator to regulate islet cell formation and function. To identify genes that are potentially regulated by Nkx2.2 during the major wave of endocrine and exocrine cell differentiation, we assessed gene expression changes that occur in the absence of Nkx2.2 at the onset of the secondary transition in the developing pancreas.ResultsMicroarray analysis identified 80 genes that were differentially expressed in e12.5 and/or e13.5 Nkx2.2-/-embryos. Some of these genes encode transcription factors that have been previously identified in the pancreas, clarifying the position of Nkx2.2 within the islet transcriptional regulatory pathway. We also identified signaling factors and transmembrane proteins that function downstream of Nkx2.2, including several that have not previously been described in the pancreas. Interestingly, a number of known exocrine genes are also misexpressed in the Nkx2.2-/-pancreas.ConclusionsExpression profiling of Nkx2.2-/-mice during embryogenesis has allowed us to identify known and novel pancreatic genes that function downstream of Nkx2.2 to regulate pancreas development. Several of the newly identified signaling factors and transmembrane proteins may function to influence islet cell fate decisions. These studies have also revealed a novel function for Nkx2.2 in maintaining appropriate exocrine gene expression. Most importantly, Nkx2.2 appears to function within a complex regulatory loop with Ngn3 at a key endocrine differentiation step.
Gene socialization: gene order, GC content and gene silencing in Salmonella
Authors: Papanikolaou Nikolas , Trachana Kalliopi , Theodosiou Theodosios , Promponas Vasilis J , Iliopoulos Ioannis 
Published: December 2009

Abstract

Background
Genes of conserved order in bacterial genomes tend to evolve slower than genes whose order is not conserved. In addition, genes with a GC content lower than the GC content of the resident genome are known to be selectively silenced by the histone-like nucleoid structuring protein (H-NS) in Salmonella.

Results
In this study, we use a comparative genomics approach to demonstrate that in Salmonella, genes whose order is not conserved (or genes without homologs) in closely related bacteria possess a significantly lower average GC content in comparison to genes that preserve their relative position in the genome. Moreover, these genes are more frequently targeted by H-NS than genes that have conserved their genomic neighborhood. We also observed that duplicated genes that do not preserve their genomic neighborhood are, on average, under less selective pressure.

Conclusions
We establish a strong association between gene order, GC content and gene silencing in a model bacterial species. This analysis suggests that genes that are not under strong selective pressure (evolve faster than others) in Salmonella tend to accumulate more AT-rich mutations and are eventually silenced by H-NS. Our findings may establish new approaches for a better understanding of bacterial genome evolution and function, using information from functional and comparative genomics.
Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies
Authors: Malvy Denis , Ezzedine Khaled , Mamani-Matsuda Maria , Autran Brigitte , Tolou Hugues , Receveur Marie-Catherine , Pistone Thierry , Rambert Jérome , Moynet Daniel , Mossalayi Djavad 
Published: December 2009

Abstract

Background
Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood.

Case presentation
We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection.

Conclusions
Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.