bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of Infectious Complications in Patients with Chronic Lymphocytic Leukemia
Authors: Morrison Vicki A. 
Published: November 2007

Abstract
Infections remain a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of these complications is related to immune defects inherent to the primary disease as well as to therapy-related immunosuppression. The spectrum of infections seen has evolved with the therapeutic use of purine analogs, which induce specific cellular immune defects, as well as the monoclonal antibodies alemtuzumab and rituximab. Although bacterial infections are most common, fungal and herpesvirus infections are also seen with use of these agents. This overview will summarize the pathogenesis of infection in patients with CLL as well as the spectrum of infection and approaches to the prophylactic and therapeutic management of these complications.
Thrombocytosis and Thrombosis
Authors: Vannucchi Alessandro M. , Barbui Tiziano 
Published: November 2007

Abstract
The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.
Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia
Authors: Pedersen-Bjergaard Jens , Andersen Morten T. , Andersen Mette K. 
Published: November 2007

Abstract
In therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), at least eight alternative genetic pathways have been defined based on characteristic recurrent chromosome abnormalities. Patients presenting as t-MDS and patients presenting as overt t-AML cluster differently in these pathways. The cytogenetic pattern depends on the type of leukemogenic therapy received: alkylating agents, topoisomerase II inhibitors, or radiotherapy.
Three types of gene mutations are observed in MDS and AML: (1) Activating mutations of genes in the tyrosine kinase–RAS/BRAF signal transduction pathway, leading to increased cell proliferation (Class I mutations); (2) Inactivating mutations of genes encoding hematopoietic transcription factors, resulting in disturbed cell differentiation (Class II mutations); and (3) Inactivating mutations of the tumor suppressor gene p53. At least 14 different genes have been identified as mutated in t-MDS and t-AML, clustering differently and characteristically in the eight genetic pathways. Class I and Class II mutations are significantly associated, indicating their cooperation in leukemogenesis
The chromosome aberrations and gene mutations detected in the therapy-related and in the de novo subsets of MDS and AML are identical, although the frequencies with which they are observed may differ. Hence, therapy-related and de novo MDS and AML are identical diseases and should be subclassified and treated similarly.
Bone Marrow Failure as a Risk Factor for Clonal Evolution: Prospects for Leukemia Prevention
Authors: Bagby Grover C. , Meyers Gabrielle 
Published: November 2007

AbstractPatients with bone marrow failure syndromes are at risk for the development of clonal neoplasms, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia (MDS), and acute myelogenous leukemia (AML). Approximately 10% to 20% of those who survive acquired aplastic anemia will develop a clonal disease within the decade following their diagnosis. The relative risk of clonal neoplasms is very significantly increased in children and adults with inherited bone marrow failure syndromes as well. Until recently, the mechanisms underlying clonal evolution have been opaque, but a sufficient amount of evidence has now accumulated to support a model in which cells resistant to extracellular apoptotic cues are selected from the stem cell pool. Indeed, in the past two years this paradigm has been validated in preclinical models that are robust enough to reconsider new therapeutic objectives in aplastic states and to support the planning and development of rationally designed leukemia prevention trials.
Philadelphia Chromosome–Positive Acute Lymphocytic Leukemia: A New Era of Challenges
Authors: Thomas Deborah A. 
Published: November 2007

AbstractSignificant advances in the treatment of Philadelephia chromosome (Ph)– or BCR-ABL–positive acute lymphocytic leukemia (ALL) have been made since the discovery of the selective ABL tyrosine kinase inhibitors (TKIs). Whereas the outcome with standard chemotherapy was previously dismal, incorporation of imatinib mesylate into frontline therapy has improved relapse-free and overall survival. The benefit of imatinib extends particularly to instances where allogeneic stem cell transplantation in first complete remission is prohibited by older age, comorbidities, or lack of a suitable donor. However, the emergence of resistance to imatinib presents new therapeutic challenges. The development of novel TKIs with enhanced inhibitory potency against ABL and other kinases may further improve on the results observed with imatinib. Optimal use of these novel agents in the treatment schema of Ph+ ALL will be paramount in ensuring continued success in the eradication of this disease. Herein, the new approaches to the management of Ph+ ALL are reviewed.
Etiology and Management of Therapy-Related Myeloid Leukemia
Authors: Larson Richard A. 
Published: November 2007

AbstractThe diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.
Limitations of Clinical Trials in Sickle Cell Disease: A Case Study of the Multi-center Study of Hydroxyurea (MSH) Trial and the Stroke Prevention (STOP) Trial
Authors: DeBaun Michael R. , Field Joshua J. 
Published: November 2007

AbstractIn the past two decades, two landmark randomized controlled trials (RCT) have been completed among individuals with sickle cell disease (SCD), the Multi-center Study of Hydroxyurea (MSH) trial and the Stroke Prevention (STOP) trial. The MSH trial tested the hypothesis that hydroxyurea will reduce the frequency of painful episodes for adults with hemoglobin SS who had a history of 3 or more painful episodes per year. The STOP trial tested the hypothesis that among children with hemoglobin SS and an elevated transcranial Doppler (TCD) velocity measurement, blood transfusion therapy would decrease the risk of an initial stroke. After completion, both trials have defined standard care for individuals with hemoglobin SS. The purpose of this review is to examine the limitations of the MSH and STOP trials. In the context of these trials, we will examine the effects of narrow inclusion criteria that primarily include participants with hemoglobin SS and secondary analyses that are prone to false-positive results. In addition, we describe how after publication of these two trials use of hydroxyurea and TCD assessment has drifted towards a standard practice without evidence of therapeutic efficacy among groups that were excluded from the trials. Finally, we suggest that rigorously conducted RCTs or at the minimum multicenter observation studies with strong methodology should be performed in these excluded subgroups to confirm a benefit of hydroxyurea or TCD measurement.
An Introduction to Foundation and Industry-Sponsored Research: Practical and Ethical Considerations
Authors: Margolin Kim A. , van Besien Koen , Peace David J. 
Published: November 2007

Abstract
Investigators face formidable challenges in securing adequate support for their research efforts. Federal subsidies for biomedical research have not expanded in the past several years, while applications to the National Institutes of Health for investigator-initiated studies have increased substantially. Faced with stiffening competition, investigators, particularly those at the outset of their careers, may consider alternative sources of funding and support. Philanthropic foundations, private donors, and commercial industry provide a diverse array of funding opportunities. Strategies to identify and solicit funding from these alternative sources are addressed herein. Emphasis is given to the development and support of investigator-initiated clinical research. Ethical considerations that frame investigators’ acceptance and utilization of research subsidies from for-profit entities, i.e., pharmaceutical or biotechnology companies, are reviewed. The importance of the protection of intellectual property and the preservation of academic integrity and autonomy, especially in the context of corporate sponsorship, also are highlighted.
GVHD—The Nuts and Bolts
Authors: Weisdorf Daniel 
Published: November 2007

Abstract
Acute graft-versus-host disease (GVHD) is the most frequent, morbid complication following allogeneic hematopoietic stem cell transplantation (HSCT). Its clinical toxicity, requirement for intensive immunosup-pressive management, and associated infections lead to the greatest risks of nonrelapse mortality in HSCT recipients. In acute GVHD, donor-derived T lymphocyte–mediated alloreactivity is complicated by inflammatory responses, cytokine release, direct tissue injury through target cell apoptosis, and secondary tissue injury. The therapeutic management includes effective GVHD prophylaxis to limit the incidence and severity of acute GVHD, prompt and effective therapy if it develops—modified if possible to protect against chronic GVHD—and intensive supportive care relevant to its association with delayed immune reconstitution. As the major ongoing morbid complication following allografting, chronic GVHD is another barrier to patients’ recovery and long-term survival. Recognition of the critical elements in the pathogenesis of GVHD has prompted new approaches to its management and its role in controlling the risks of malignant relapse after allotransplantation. Important elements in the practical management of GVHD will be reviewed.
The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma
Authors: Chatterjee Manik , Rancso Christoph , Stühmer Thorsten , Eckstein Niels , Andrulis Mindaugas , Gerecke Christian , Lorentz Heike , Royer Hans-Dieter , Bargou Ralf C. 
Published: November 2007

Abstract
Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y-box binding protein YB-1 in MM. YB-1 is a member of the cold-shock domain protein superfamily and involved in various cellular functions such as proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS), nor MM cells with a mature morphology showed expression of YB-1 in situ. In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1–expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced apoptosis in MM cells even in the presence of BM stromal cells. Furthermore, we found that overexpression of YB-1 mediated resistance toward doxorubicin-induced apoptosis in MM cells. Thus, YB-1 contributes to disease progression, survival, and drug resistance in MM and might therefore provide an attractive therapeutic target.
Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis
Authors: Sellick Gabrielle S. , Wade Rachel , Richards Susan , Oscier David G. , Catovsky Daniel , Houlston Richard S. 
Published: November 2007

AbstractTo identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgVH) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available.
Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3)
Authors: You Ren-In , Chang Yung-Chi , Chen Po-Min , Wang Wei-Shu , Hsu Tsui-Ling , Yang Chih-Ya , Lee Chun-Ting , Hsieh Shie-Liang 
Published: November 2007

Abstract
Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, and its expression is not only up-regulated in cancer cells derived from various cell lineages, but also correlates with overall survival of patients with cancer. It has been shown that DcR3 sensitize cells of hematopoietic origin to TNF-related apoptosis-inducing ligand (TRAIL)–induced apoptosis; therefore, we asked whether DcR3 down-regulated host immunity by inducing immune cell apoptosis. We demonstrate that DcR3 induces dendritic cell (DC) apoptosis by activating PKC-δ and JNK subsequently to up-regulate DR5 to recruit Fas-associated death domain (FADD) to propagate the apoptotic signals. The association of FADD with DR5 results in the formation of death-inducing signaling complex (DISC) to trigger the downstream apoptotic signaling cascade. PKC-δ is activated via cross-linking of heparan sulfate proteoglycan (HSPG) on DCs, because recombinant protein containing the heparin-binding domain (HBD) of DcR3 and the Fc portion of IgG1, the HBD.Fc fusion protein, is also able to trigger DC apoptosis. This provides the first evidence that cross-linking of HSPG on DCs can activate PKC-δ to induce DC apoptosis via the formation of DR5 DISC, and elucidates a novel mechanism of DcR3-mediated immunosuppression.
Peptide ligand screening of α-synuclein aggregation modulators by in silico panning
Authors: Abe Koichi , Kobayashi Natsuki , Sode Koji , Ikebukuro Kazunori 
Published: November 2007

Abstract

Background
α-Synuclein is a Parkinson's-disease-related protein. It forms aggregates in vivo, and these aggregates cause cell cytotoxicity. Aggregation inhibitors are expected to reduce α-synuclein cytotoxicity, and an aggregation accelerator has recently been reported to reduce α-synuclein cytotoxicity. Therefore, amyloid aggregation modulating ligands are expected to serve as therapeutic medicines.

Results
We screened peptide ligands against α-synuclein by in silico panning, a method which we have proposed previously. In this study, we selected as the target a very hydrophobic region known as the amyloid-core-forming region. Since this region cannot be dissolved in water, it is difficult to carry out the in vitro screening of its peptide ligand. We carried out 6 rounds of in silico panning using a genetic algorithm and a docking simulation. After the in silico panning, we evaluated the top peptides screened in silico by in vitro assay. These peptides were capable of binding to α-synuclein.

Conclusion
We demonstrated that it is possible to screen α-synuclein-binding peptides by in silico panning. The screened peptides bind to α-synuclein, thus affecting the aggregation of α-synuclein.
The [FeFe] hydrogenase of Nyctotherus ovalis has a chimeric origin
Authors: Boxma Brigitte , Ricard Guenola , van Hoek Angela HAM , Severing Edouard , Moon-van der Staay Seung-Yeo , van der Staay Georg WM , van Alen Theo A , de Graaf Rob M , Cremers Geert , Kwantes Michiel , McEwan Neil R , Newbold C Jamie , Jouany Jean-Pierre , Michalowski Tadeusz , Pristas Peter , Huynen Martijn A , Hackstein Johannes HP 
Published: November 2007

Abstract

Background
The hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis show how mitochondria can evolve into hydrogenosomes because they possess a mitochondrial genome and parts of an electron-transport chain on the one hand, and a hydrogenase on the other hand. The hydrogenase permits direct reoxidation of NADH because it consists of a [FeFe] hydrogenase module that is fused to two modules, which are homologous to the 24 kDa and the 51 kDa subunits of a mitochondrial complex I.

Results
The [FeFe] hydrogenase belongs to a clade of hydrogenases that are different from well-known eukaryotic hydrogenases. The 24 kDa and the 51 kDa modules are most closely related to homologous modules that function in bacterial [NiFe] hydrogenases. Paralogous, mitochondrial 24 kDa and 51 kDa modules function in the mitochondrial complex I in N. ovalis. The different hydrogenase modules have been fused to form a polyprotein that is targeted into the hydrogenosome.

Conclusion
The hydrogenase and their associated modules have most likely been acquired by independent lateral gene transfer from different sources. This scenario for a concerted lateral gene transfer is in agreement with the evolution of the hydrogenosome from a genuine ciliate mitochondrion by evolutionary tinkering.
Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response
Authors: Qiao Xingwen , Lu Jui-Yun , Hofmann Sandra L 
Published: November 2007

Abstract

Background
The infantile form of neuronal ceroid lipofuscinosis (also known as infantile Batten disease) is caused by hereditary deficiency of a lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1), and is characterized by severe cortical degeneration with blindness and cognitive and motor dysfunction. The PPT1-deficient knockout mouse recapitulates the key features of the disorder, including seizures and death by 7–9 months of age. In the current study, we compared gene expression profiles of whole brain from PPT1 knockout and normal mice at 3, 5 and 8 months of age to identify temporal changes in molecular pathways implicated in disease pathogenesis.

Results
A total of 267 genes were significantly (approximately 2-fold) up- or downregulated over the course of the disease. Immediate early genes (Arc, Cyr61, c-fos, jun-b, btg2, NR4A1) were among the first genes upregulated during the presymptomatic period whereas immune response genes dominated at later time points. Chemokine ligands and protease inhibitors were among the most transcriptionally responsive genes. Neuronal survival factors (IGF-1 and CNTF) and a negative regulator of neuronal apoptosis (DAP kinase-1) were upregulated late in the course of the disease. Few genes were downregulated; these included the α2 subunit of the GABA-A receptor, a component of cortical and hippocampal neurons, and Hes5, a transcription factor important in neuronal differentiation.

Conclusion
A molecular description of gene expression changes occurring in the brain throughout the course of neuronal ceroid lipofuscinosis suggests distinct phases of disease progression, provides clues to potential markers of disease activity, and points to new targets for therapy.