bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient differentiation and function of human macrophages in humanized CSF-1 mice
Authors: Rathinam Chozhavendan , Poueymirou William T. , Rojas Jose , Murphy Andrew J. , Valenzuela David M. , Yancopoulos George D. , Rongvaux Anthony , Eynon Elizabeth E. , Manz Markus G. , Flavell Richard A. 
Published: July 2011

AbstractHumanized mouse models are useful tools to understand pathophysiology and to develop therapies for human diseases. While significant progress has been made in generating immunocompromised mice with a human hematopoietic system, there are still several shortcomings, one of which is poor human myelopoiesis. Here, we report that human CSF-1 knockin mice show augmented frequencies and functions of human myeloid cells. Insertion of human CSF1 into the corresponding mouse locus of Balb/c Rag2−/− γc−/− mice through VELOCIGENE technology resulted in faithful expression of human CSF-1 in these mice both qualitatively and quantitatively. Intra-hepatic transfer of human fetal liver derived hematopoietic stem and progenitor cells (CD34+) in humanized CSF-1 (CSF1h/h) newborn mice resulted in more efficient differentiation and enhanced frequencies of human monocytes/macrophages in the bone marrow, spleens, peripheral blood, lungs, liver and peritoneal cavity. Human monocytes/macrophages obtained from the humanized CSF-1 mice show augmented functional properties including migration, phagocytosis, activation and responses to LPS. Thus, humanized mice engineered to express human cytokines will significantly help to overcome the current technical challenges in the field. In addition, humanized CSF-1 mice will be a valuable experimental model to study human myeloid cell biology.
Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients
Authors: Curti Antonio , Ruggeri Loredana , D'Addio Alessandra , Bontadini Andrea , Dan Elisa , Motta Maria Rosa , Trabanelli Sara , Giudice Valeria , Urbani Elena , Martinelli Giovanni , Paolini Stefania , Fruet Fiorenza , Isidori Alessandro , Parisi Sarah , Bandini Giuseppe , Baccarani Michele , Velardi Andrea , Lemoli Roberto M. 
Published: July 2011

Abstract
Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56+CD3− natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor–ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 106/Kg. T cells were < 105/Kg. No NK cell–related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799.
In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions
Authors: Agostinis Chiara , Biffi Stefania , Garrovo Chiara , Durigutto Paolo , Lorenzon Andrea , Bek Alpan , Bulla Roberta , Grossi Claudia , Borghi Maria O. , Meroni PierLuigi , Tedesco Francesco 
Published: July 2011

Abstract
In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.
Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease
Authors: Chomel Jean-Claude , Bonnet Marie-Laure , Sorel Nathalie , Bertrand Angelina , Meunier Marie-Claude , Fichelson Serge , Melkus Michael , Bennaceur-Griscelli Annelise , Guilhot François , Turhan Ali G. 
Published: July 2011

Abstract
Sustained undetectable molecular residual disease (UMRD) is obtained in a minority of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. It remains unclear whether these patients are definitively cured of their leukemia or whether leukemic stem cells (LSCs) persist in their BM. We have evaluated the presence of BCR-ABL–expressing marrow LSCs in 6 patients with chronic myeloid leukemia with sustained UMRD induced by IFN-α (n = 3), imatinib mesylate after IFN-α failure (n = 2), and dasatinib after imatinib intolerance (n = 1). Purified CD34+ cells were used for clonogenic and long-term culture-initiating cell assays performed on classic or HOXB4-expressing MS-5 feeders. Using this strategy, we identified BCR-ABL–expressing LSCs in all patients. Interestingly, long-term culture-initiating cell assays with MS-5/HOXB4 stromal feeders increased detected numbers of LSCs in 3 patients. The relation between LSC persistency and a potential risk of disease relapse for patients with durable UMRD (on or off tyrosine kinase inhibitor therapy) warrants further investigation.
Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis
Authors: Noubade Rajkumar , Krementsov Dimitry N. , del Rio Roxana , Thornton Tina , Nagaleekar Viswas , Saligrama Naresha , Spitzack Anthony , Spach Karen , Sabio Guadalupe , Davis Roger J. , Rincon Mercedes , Teuscher Cory 
Published: July 2011

AbstractAlthough several transcription factors have been shown to be critical for the induction and maintenance of IL-17 expression by CD4 Th cells, less is known about the role of nontranscriptional mechanisms. Here we show that the p38 MAPK signaling pathway is essential for in vitro and in vivo IL-17 production by regulating IL-17 synthesis in CD4 T cells through the activation of the eukaryotic translation initiation factor 4E/MAPK-interacting kinase (eIF-4E/MNK) pathway. We also show that p38 MAPK activation is required for the development and progression of both chronic and relapsing-remitting forms of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis. Furthermore, we show that regulation of p38 MAPK activity specifically in T cells is sufficient to modulate EAE severity. Thus, mechanisms other than the regulation of gene expression also contribute to Th17 cell effector functions and, potentially, to the pathogenesis of other Th17 cell–mediated diseases.
Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases
Authors: Hadzidimitriou Anastasia , Agathangelidis Andreas , Darzentas Nikos , Murray Fiona , Delfau-Larue Marie-Helene , Pedersen Lone Bredo , Lopez Alba Navarro , Dagklis Antonis , Rombout Paul , Beldjord Kheira , Kolstad Arne , Dreyling Martin H. , Anagnostopoulos Achilles , Tsaftaris Athanasios , Mavragani-Tsipidou Penelope , Rosenwald Andreas , Ponzoni Maurilio , Groenen Patricia , Ghia Paolo , Sander Birgitta , Papadaki Theodora , Campo Elias , Geisler Christian , Rosenquist Richard , Davi Frederic , Pott Christiane , Stamatopoulos Kostas 
Published: July 2011

AbstractWe examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were “MCL-biased.” In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.
Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection
Authors: Reeves R. Keith , Rajakumar Premeela A. , Evans Tristan I. , Connole Michelle , Gillis Jacqueline , Wong Fay E. , Kuzmichev Yury V. , Carville Angela , Johnson R. Paul 
Published: July 2011

Abstract
Natural killer (NK) cells are classically viewed as effector cells that kill virus-infected and neoplastic cells, but recent studies have identified a rare mucosal NK- cell subpopulation secreting the TH17 cytokine IL-22. Here, we report identification of 2 distinct lineages of mucosal NK cells characterized as NKG2A+NFIL3+RORC– and NKp44+NFIL3+RORC+. NKG2A+ NK cells were systemically distributed, cytotoxic, and secreted IFN-γ, whereas NKp44+ NK cells were mucosae-restricted, noncytotoxic, and produced IL-22 and IL-17. During SIV infection, NKp44+ NK cells became apoptotic, were depleted, and had an altered functional profile characterized by decreased IL-17 secretion; increased IFN-γ secretion; and, surprisingly, increased potential for cytotoxicity. NKp44+ NK cells showed no evidence of direct SIV infection; rather, depletion and altered function were associated with SIV-induced up-regulation of inflammatory mediators in the gut, including indoleamine 2,3-dioxygenase 1. Furthermore, treatment of NKp44+ NK cells with indoleamine 2,3-dioxygenase 1 catabolites in vitro ablated IL-17 production in a dose-dependent manner, whereas other NK-cell functions were unaffected. Thus lentiviral infection both depletes and modifies the functional repertoire of mucosal NK cells involved in the maintenance of gut integrity, a finding that highlights the plasticity of this rare mucosal NK-cell population.
The miR-144/451eGFP allele, a novel tool for resolving the erythroid potential of hematopoietic precursors
Authors: Rasmussen Kasper D. , O'Carroll Dónal 
Published: July 2011

AbstractA long outstanding problem is the resolution of the full potential of hematopoietic precursors. The commonly used allotypic marker Ly5 permits the tracing of lymphoid and granulocyte-macrophage (GM) output. Here we present a novel eGFP allele that allows the quantitative analysis of red blood cell (RBC) origin at the single-cell level. The miR-144/451 locus is required for erythroid development and homeostasis. Taking advantage of the fact that miR-451 is specifically and highly expressed in the erythroid lineage, we inserted an eGFP expression cassette into the miR-144/451 locus. In miR-144/451+/eGFP animals, accumulation of eGFP is exclusively observed during terminal erythroid differentiation. Expression of miR-144/451eGFP ignites immediately before the CFU-E stage and results in strong and complete labeling of all mature RBCs in circulation. Using competitive reconstitution experiments in the Ly5 transplant model, we show that eGFP linearly correlates with Ly5 expression. Thus, the miR-144/451eGFP allele represents a novel tool for the resolution of erythroid potential.
Approach to the treatment of multiple myeloma: a clash of philosophies
Authors: Rajkumar S. Vincent , Gahrton Gösta , Bergsagel P. Leif 
Published: July 2011

Abstract
In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice.
Bayesian semi-supervised classification of bacterial samples using MLST databases
Authors: Cheng Lu , Connor Thomas R , Aanensen David M , Spratt Brian G , Corander Jukka 
Published: July 2011

AbstractBackgroundWorldwide effort on sampling and characterization of molecular variation within a large number of human and animal pathogens has lead to the emergence of multi-locus sequence typing (MLST) databases as an important tool for studying the epidemiology and evolution of pathogens. Many of these databases are currently harboring several thousands of multi-locus DNA sequence types (STs) enriched with metadata over traits such as serotype, antibiotic resistance, host organism etc of the isolates. Curators of the databases have thus the possibility of dividing the pathogen populations into subsets representing different evolutionary lineages, geographically associated groups, or other subpopulations, which are defined in terms of molecular similarities and dissimilarities residing within a database. When combined with the existing metadata, such subsets may provide invaluable information for assessing the position of a new set of isolates in relation to the whole pathogen population.ResultsTo enable users of MLST schemes to query the databases with sets of new bacterial isolates and to automatically analyze their relation to existing curated sequences, we introduce here a Bayesian model-based method for semi-supervised classification of MLST data. Our method can use an MLST database as a training set and assign simultaneously any set of query sequences into the earlier discovered lineages/populations, while also allowing some or all of these sequences to form previously undiscovered genetically distinct groups. This tool provides probabilistic quantification of the classification uncertainty and is highly efficient computationally, thus enabling rapid analyses of large databases and sets of query sequences. The latter feature is a necessary prerequisite for an automated access through the MLST web interface. We demonstrate the versatility of our approach by anayzing both real and synthesized data from MLST databases. The introduced method for semi-supervised classification of sets of query STs is freely available for Windows, Mac OS X and Linux operative systems in BAPS 5.4 software which is downloadable athttp://web.abo.fi/fak/mnf/mate/jc/software/baps.html. The query functionality is also directly available for theStaphylococcus aureusdatabase athttp://www.mlst.netand shortly will be available for other species databases hosted at this web portal.ConclusionsWe have introduced a model-based tool for automated semi-supervised classification of new pathogen samples that can be integrated into the web interface of the MLST databases. In particular, when combined with the existing metadata, the semi-supervised labeling may provide invaluable information for assessing the position of a new set of query strains in relation to the particular pathogen population represented by the curated database.Such information will be useful both for clinical and basic research purposes.
Inactivation and sub-lethal injury of salmonella typhi, salmonella typhimurium and vibrio cholerae in copper water storage vessels
Authors: Sharan Riti , Chhibber Sanjay , Reed Robert H 
Published: July 2011

Abstract

Background
This study provides information on the antibacterial effect of copper against the water-borne pathogens Salmonella Typhi, Salmonella Typhimurium and Vibrio cholerae.

Methods
Suspensions of each pathogen were kept in water within a traditional copper vessel at 30°C for 24 h. Samples were withdrawn, diluted and plated onto suitable growth media. Conventional enumeration of healthy (uninjured) bacteria was carried out using standard aerobic incubation conditions. Additionally, reactive oxygen species-neutralised (ROS-n) conditions were achieved by adding the peroxide scavenger sodium pyruvate to the medium with anaerobic incubation, to enumerate uninjured (ROS-insensitive) and injured (ROS-sensitive) bacteria. Differences between log-transformed means of conventional (aerobic) and ROS-n counts were statistically evaluated using t tests.

Results
Overall, all three pathogens were inactivated by storage in copper vessels for 24 h. However, for shorter-term incubation (4-12 h), higher counts were observed under ROS-n conditions than under aerobic conditions, which demonstrate the presence of substantial numbers of sub-lethally injured cells prior to their complete inactivation.

Conclusions
The present study has for the first time confirmed that these bacterial pathogens are inactivated by storage in a copper vessel within 24 h. However, it has also demonstrated that it is necessary to account for short-term sub-lethal injury, manifest as ROS-sensitivity, in order to more fully understand the process. This has important practical implications in terms of the time required to store water within a copper vessel to completely inactivate these bacteria and thereby remove the risk of water-borne disease transmission by this route.
A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes
Authors: Della-Morte David , Beecham Ashley , Rundek Tatjana , Wang Liyong , McClendon Mark S , Slifer Susan , Blanton Susan H , Di Tullio Marco R , Sacco Ralph L 
Published: July 2011

Abstract

Background
Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM.

Methods
Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets.

Results
In the overall analysis, the most significant association was found to rs10743465, downstream of the SOX5 gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in β coefficients), located upstream of TMTC1. Twelve additional SNPs in or near 6 genes had p < 0.001.

Conclusions
The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. SOX5 may play an important role in the regulation of LVM. An interaction of TMTC1 with abdominal obesity may contribute to phenotypic variation of LVM.
Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy
Authors: Maurer Gabriele D , Brucker Daniel P , Bähr Oliver , Harter Patrick N , Hattingen Elke , Walenta Stefan , Mueller-Klieser Wolfgang , Steinbach Joachim P , Rieger Johannes 
Published: July 2011

AbstractBackgroundEven in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells.MethodsTo investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterizedin vitroeffects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines.In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.ResultsThe ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated.In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.ConclusionIn summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodiesin vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.