bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel therapies for relapsed myeloma
Authors: Stewart A. Keith 
Published: December 2009

AbstractTreatment of myeloma relapse needs to be individualized to reflect the effectiveness and toxicities of prior therapies, with consideration given to pragmatic issues such as the tempo of relapse, age of the patient, access to drugs and patient preference. In general, combination therapies have been associated with higher response rates and improved progression-free survival and may be preferable when a rapid response is required. Nevertheless, in a slower-tempo relapse it is unclear at this juncture whether sequencing of drugs or multi-agent combinations offer superior overall survival results. Fortunately, active novel agents that offer further possibilities for some myeloma patients have become available in clinical trials. In this review we will describe the various classes of novel drugs being tested and the pros and cons of preclinical testing, and will particularly focus on two agents with single-agent activity in myeloma: carfilzomib, a proteasome inhibitor, and pomalidomide, a member of the immunomodulatory class of drugs.
Advances in the use of hydroxyurea
Authors: Ware Russell E. , Aygun Banu 
Published: December 2009

Abstract
Clinical experience with hydroxyurea for patients with sickle cell disease (SCD) has been accumulating for the past 25 years. The bulk of the current evidence suggests that hydroxyurea is well-tolerated, safe, and efficacious for most patients with SCD. Hydroxyurea has proven clinical efficacy for reducing acute vaso-occlusive events including pain episodes and acute chest syndrome. Salutary effects on hematological parameters include increases in fetal hemoglobin (HbF), hemoglobin, and MCV; also significant decreases occur in WBC, ANC, reticulocytes, LDH, and bilirubin. Treatment with hydroxyurea is usually considered for patients with recurrent vaso-occlusive events, but additional indications for treatment may include laboratory markers of disease severity and evidence of chronic organ dysfunction. Ten years ago, the US Food and Drug Administration approved hydroxyurea for adult patients with clinically severe SCD; however, its use in children remains off-label. Despite the large body of evidence regarding its efficacy and safety, hydroxyurea is currently prescribed only sparingly for patients with SCD and therefore has only limited effectiveness for this disorder; barriers to its use need to be identified and overcome.
Pathogenesis and management of essential thrombocythemia
Authors: Beer Philip A. , Green Anthony R. 
Published: December 2009

Abstract
The last four years have seen an explosion in our understanding of the myeloproliferative neoplasms. Important and often unexpected insights into the molecular mechanisms responsible for these disorders have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between the different disease entities. This review will focus on recent developments in the pathogenesis and management of essential thrombocythemia with a particular emphasis on its phenotypic overlap with polycythemia vera and primary myelofibrosis.
Idiopathic erythrocytosis: a disappearing entity
Authors: McMullin Mary Frances 
Published: December 2009

Abstract
Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. Congenital causes include mutations of the erythropoietin receptor and defects of the oxygen-sensing pathway including VHL, PHD2 and HIF2A mutations. When fully investigated there remain a number of patients in whom no cause can be elucidated who are currently described as having idiopathic erythrocytosis. Investigation should start with a full history and examination. Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.
Treatment of MDS: something old, something new, something borrowed…
Authors: Sekeres Mikkael A. 
Published: December 2009

AbstractAs opposed to the treatment landscape for myelodysplastic syndromes (MDS) two decades ago, potential therapies now abound for the treatment of lower-risk and higher-risk populations. In lower-risk patients, decision tools can be used to determine the likelihood of response to erythropoiesis stimulating agents (ESAs), which have demonstrated survival advantages in retrospective studies in patients with MDS, and whether these patients should be treated initially with ESAs or non-growth factor (“active”) therapies. Lenalidomide has shown good activity in transfusion-dependent patients with the del(5q) cytogenetic abnormality and modest activity in other lower-risk patients. In higher-risk patients, the DNA methyltransferase inhibitors produce complete and partial responses in 20% to 30% of patients, and for the first time, the MDS drug azacitidine has demonstrated a survival advantage when compared with conventional therapies. Newer therapies stimulate platelet production and target novel pathways, while a panoply of combination studies are underway or recently completed and that likely represent the next frontier in MDS therapy.
Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders
Authors: Persons Derek A. 
Published: December 2009

Abstract
Hematopoietic stem cell (HSC)–targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of β-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for β-thalassemia has begun in France, and one patient with transfusion-dependent HbE/β-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34+ cells genetically modified with a β-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.
Imaging circulating cells and lymphoid tissues with iron oxide nanoparticles
Authors: Elias Andrew , Tsourkas Andrew 
Published: December 2009

Abstract
The use of nanometer-sized iron oxide nanoparticles and micron-sized iron oxide particles as magnetic resonance (MR) contrast agents has garnered a high degree of interest in diverse areas of biology and medicine. Applications such as cell tracking, molecular imaging, gene detection, and lymphography are being explored to provide insight into disease mechanisms, monitor therapeutic efficacy, and facilitate diagnostic imaging. What makes iron oxide so appealing is a number of favorable properties including high detectability by MR, biodegradability and low toxicity. Here we describe the recent progress on the use of magnetic nanoparticles in imaging circulating cells and lymphoid tissues. The study of the lymph system and the biodistribution of various circulating immune cells is important in the diagnosis, prognosis, and treatment of a wide range of diseases and is expected to have a profound effect on patient outcome.
Finding the right academic job
Authors: Ghobrial Irene M. , Laubach Jacob P. , Soiffer Robert J. 
Published: December 2009

Abstract
The career path in academic medicine is full of exciting opportunities as well as great achievements and discoveries. In this review, we discuss various obstacles that fellows face as they explore career opportunities in academic hematology/oncology. We also share thoughts on what might be considered steps for success in maneuvering through a search for the “right” position. We discuss several aims including how to define career goals early on, keys to success in an academic career, how to look for an academic job, successful points for the interview process, and how to negotiate a job offer. Finally, we discuss some roadblocks and limitations of academic careers and promotions. These limitations, frustrations and roadblocks should not be a deterrent from pursuing such a great role in the scientific field. This is a new generation of scientific discovery, improvement in healthcare and great advances in research.
The academic job offer: what to expect and how to negotiate
Authors: Schafer Andrew I. 
Published: December 2009

Abstract
In contrast to the familiar college, medical school, residency and fellowship application mechanisms, securing the first academic faculty position has no ground rules and no timelines. The open-ended and idiosyncratic nature of securing a job can be frustrating. Negotiating a competitive start-up package when continuing on the faculty of one’s training institution can be particularly challenging. Deciding which offer to accept should be determined less by the “best deal” that can be negotiated and more by the short-term and long-term opportunities for career success.
Academic promotion and tenure: a user’s guide for junior faculty members
Authors: Buchanan George R. 
Published: December 2009

Abstract
Securing a junior faculty position is an important early step in an academic career in hematology. Shortly thereafter one should begin to plan for eventual promotion and possible tenure. The process is not straightforward, as the “rules of the road” regarding academic positions, academic tracks, assessment and evaluation metrics, and timelines vary immensely from one institution to another. It is critically important, therefore, for the new junior faculty member to become knowledgeable about the institutional policies and “culture” regarding this process. This understanding includes the definition of and criteria for achieving tenure, the academic tracks and the policies for advancement on each track, and the process by which the institutional committee responsible for promotion and tenure conducts its activities. Learning the rules and successfully navigating the academic pathway will help ensure success by achieving the desired promotion and the self-satisfaction, prestige, and financial awards that may accompany it.
Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia
Authors: Muramatsu Hideki , Makishima Hideki , Jankowska Anna M. , Cazzolli Heather , O'Keefe Christine , Yoshida Nao , Xu Yinyan , Nishio Nobuhiro , Hama Asahito , Yagasaki Hiroshi , Takahashi Yoshiyuki , Kato Koji , Manabe Atsushi , Kojima Seiji , Maciejewski Jaroslaw P. 
Published: December 2009

Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypes showed earlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients.
A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo
Authors: Fehr Thomas , Lucas Carrie L. , Kurtz Josef , Onoe Takashi , Zhao Guiling , Hogan Timothy , Vallot Casey , Rao Anjana , Sykes Megan 
Published: December 2009

AbstractPrevious studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1−/− mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell–intrinsic NFAT1 requirement for CD8 tolerance in vivo.
FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML
Authors: Pratz Keith W. , Sato Takashi , Murphy Kathleen M. , Stine Adam , Rajkhowa Trivikram , Levis Mark 
Published: December 2009

AbstractWe examined 6 different FMS-like tyrosine kinase-3 (FLT3) inhibitors (lestaurtinib, midostaurin, AC220, KW-2449, sorafenib, and sunitinib) for potency against mutant and wild-type FLT3, as well as for cytotoxic effect against a series of primary blast samples obtained from patients with acute myeloid leukemia (AML) harboring internal tandem duplication (FLT3/ITD) mutations. We found that inhibition of FLT3 autophosphorylation in a FLT3/ITD specimen does not always induce cell death, suggesting that some FLT3/ITD AML may not be addicted to FLT3 signaling. Relapsed samples and samples with a high mutant allelic burden were more likely to be responsive to cytotoxicity from FLT3 inhibition compared with the samples obtained at diagnosis or those with a low mutant allelic burden. These FLT3 inhibitors varied to a considerable degree in their selectivity for FLT3, and this selectivity influenced the cytotoxic effect. These results have important implications for the potential therapeutic use of FLT3 inhibitors in that patients with newly diagnosed FLT3-mutant AML might be less likely to respond clinically to highly selective FLT3 inhibition.
A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell–mediated responses that are differentially sensitive to therapy
Authors: Chow Leola , Aslam Rukhsana , Speck Edwin R. , Kim Michael , Cridland Norman , Webster Michelle Lee , Chen Pingguo , Sahib Kim , Ni Heyu , Lazarus Alan H. , Garvey M. Bernadette , Freedman John , Semple John W. 
Published: December 2009

AbstractImmune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61+ platelets were transferred into severe combined immunodeficient (SCID) (CD61+) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 × 104 splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4+ T helper cells and that both CD19+ B cell (antibody)– and CD8+ T cell (cell)–mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous γ-globulins raised platelet counts and completely prevented bleeding mortality induced by antibody-mediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody- and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy.
Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia
Authors: Silverman Lewis B. , Supko Jeffrey G. , Stevenson Kristen E. , Woodward Christina , Vrooman Lynda M. , Neuberg Donna S. , Asselin Barbara L. , Athale Uma H. , Clavell Luis , Cole Peter D. , Kelly Kara M. , Laverdière Caroline , Michon Bruno , Schorin Marshall , Schwartz Cindy L. , O'Brien Jane E. , Cohen Harvey J. , Sallan Stephen E. 
Published: December 2009

AbstractOver the past several decades, L-asparaginase, an important component of therapy for acute lymphoblastic leukemia (ALL), has typically been administered intramuscularly rather than intravenously in North America because of concerns regarding anaphylaxis. We evaluated the feasibility of giving polyethylene glycosylated (PEG)–asparaginase, the polyethylene glycol conjugate of Escherichia coli L-asparaginase, by intravenous infusion in children with ALL. Between 2005 and 2007, 197 patients (age, 1-17 years) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-01 and received a single dose of intravenous PEG-asparaginase (2500 IU/m2) over 1 hour during remission induction. Serum asparaginase activity more than 0.1 IU/mL was detected in 95%, 88%, and 7% of patients at 11, 18, and 25 days after dosing, respectively. Toxicities included allergy (1.5%), venous thrombosis (2%), and pancreatitis (4.6%). We conclude that intravenous administration of PEG-asparaginase is tolerable in children with ALL, and potentially therapeutic enzyme activity is maintained for at least 2 weeks after a single dose in most patients. This trial was registered at www.clinicaltrials.gov as #NCT00400946.
Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis
Authors: Santos Fabio P. S. , Kantarjian Hagop M. , Jain Nitin , Manshouri Taghi , Thomas Deborah A. , Garcia-Manero Guillermo , Kennedy Debra , Estrov Zeev , Cortes Jorge , Verstovsek Srdan 
Published: December 2009

Abstract
Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2V617F) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2V617F-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2V617F allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.
The transcriptional programme of Salmonella enterica serovar Typhimurium reveals a key role for tryptophan metabolism in biofilms
Authors: Hamilton Shea , Bongaerts Roy JM , Mulholland Francis , Cochrane Brett , Porter Jonathan , Lucchini Sacha , Lappin-Scott Hilary M , Hinton Jay CD 
Published: December 2009

Abstract

Background
Biofilm formation enhances the capacity of pathogenic Salmonella bacteria to survive stresses that are commonly encountered within food processing and during host infection. The persistence of Salmonella within the food chain has become a major health concern, as biofilms can serve as a reservoir for the contamination of food products. While the molecular mechanisms required for the survival of bacteria on surfaces are not fully understood, transcriptional studies of other bacteria have demonstrated that biofilm growth triggers the expression of specific sets of genes, compared with planktonic cells. Until now, most gene expression studies of Salmonella have focused on the effect of infection-relevant stressors on virulence or the comparison of mutant and wild-type bacteria. However little is known about the physiological responses taking place inside a Salmonella biofilm.

Results
We have determined the transcriptomic and proteomic profiles of biofilms of Salmonella enterica serovar Typhimurium. We discovered that 124 detectable proteins were differentially expressed in the biofilm compared with planktonic cells, and that 10% of the S. Typhimurium genome (433 genes) showed a 2-fold or more change in the biofilm compared with planktonic cells. The genes that were significantly up-regulated implicated certain cellular processes in biofilm development including amino acid metabolism, cell motility, global regulation and tolerance to stress. We found that the most highly down-regulated genes in the biofilm were located on
S

almonella
P athogenicity I sland 2 (SPI2), and that a functional SPI2 secretion system regulator (ssrA) was required for S. Typhimurium biofilm formation. We identified STM0341 as a gene of unknown function that was needed for biofilm growth. Genes involved in tryptophan (trp) biosynthesis and transport were up-regulated in the biofilm. Deletion of trpE led to decreased bacterial attachment and this biofilm defect was restored by exogenous tryptophan or indole.

Conclusions
Biofilm growth of S. Typhimurium causes distinct changes in gene and protein expression. Our results show that aromatic amino acids make an important contribution to biofilm formation and reveal a link between SPI2 expression and surface-associated growth in S. Typhimurium.