77 research outputs found
Measurement of Charged Pion Production Yields off the NuMI Target
The fixed-target MIPP experiment, Fermilab E907, was designed to measure the
production of hadrons from the collisions of hadrons of momenta ranging from 5
to 120 GeV/c on a variety of nuclei. These data will generally improve the
simulation of particle detectors and predictions of particle beam fluxes at
accelerators. The spectrometer momentum resolution is between 3 and 4%, and
particle identification is performed for particles ranging between 0.3 and 80
GeV/c using , time-of-flight and Cherenkov radiation measurements. MIPP
collected events of 120 GeV Main Injector protons striking a
target used in the NuMI facility at Fermilab. The data have been analyzed and
we present here charged pion yields per proton-on-target determined in bins of
longitudinal and transverse momentum between 0.5 and 80 GeV/c, with combined
statistical and systematic relative uncertainties between 5 and 10%.Comment: 15 pages, 13 figure
FAS promoter polymorphism: outcome of childhood acute myeloid leukemia. A children's oncology group report.
PURPOSE: FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down-regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine transition in the FAS promoter region (position -1377) is thought to reduce stimulatory protein 1 transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at -1,377 bp significantly attenuates transcription factor stimulatory protein 1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might affect outcome of childhood AML therapy. EXPERIMENTAL DESIGN: Four hundred forty-four children treated for de novo AML on a uniform protocol were genotyped for FAS 1377. RESULTS: There were no significant differences in overall survival, event-free survival, treatment-related mortality, or relapse rate between patients with FAS 1377GG genotype versus 1377GA/1377AA genotypes. CONCLUSIONS: FAS 1377 genotype does not alter outcome of de novo AML in children
Bone marrow stromal cells attenuate sepsis via prostaglandin E2Γ’β¬β dependent reprogramming of host macrophages to increase their interleukin-10 production
Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCsΓ’β¬βalso known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/ or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF)
receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-ΓΒ±) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the
prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.Sepsis, a serious medical condition that affects 18 million people per year worldwide, is characterized by a generalized inflammatory state caused by infection. Widespread activation of inflammation and coagulation pathways progresses to multiple organ dysfunction, collapse of the circulatory system (septic shock) and death. Because as many people die of sepsis annually as from acute myocardial infarction1, a new treatment regimen is desperately needed.
In the last few years, it has been discovered that BMSCs are potent modulators of immune responses2-5. We wondered whether such cells could bring the immune response back into balance, thus attenuating the underlying pathophysiology that eventually leads to severe sepsis,
septic shock and death6,7. As a model of sepsis, we chose cecal ligation and puncture (CLP), a procedure that has been used for more than two decades8. This mouse model closely resembles the human disease: it has a focal origin (cecum), is caused by multiple intestinal organisms, and results in septicemia with release of bacterial toxins into the circulation. With no treatment, the majority of the mice die 24-48 h postoperatively. Originally published Nature Medicine, Vol. 15, No. 1, Jan 200
Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT)
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived βnullβ variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5Γ10β8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS
A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans
Several genetic variants associated with platelet count and mean platelet volume
(MPV) were recently reported in people of European ancestry. In this
meta-analysis of 7 genome-wide association studies (GWAS) enrolling African
Americans, our aim was to identify novel genetic variants associated with
platelet count and MPV. For all cohorts, GWAS analysis was performed using
additive models after adjusting for age, sex, and population stratification. For
both platelet phenotypes, meta-analyses were conducted using inverse-variance
weighted fixed-effect models. Platelet aggregation assays in whole blood were
performed in the participants of the GeneSTAR cohort. Genetic variants in ten
independent regions were associated with platelet count
(Nβ=β16,388) with p<5Γ10β8 of
which 5 have not been associated with platelet count in previous GWAS. The novel
genetic variants associated with platelet count were in the following regions
(the most significant SNP, closest gene, and p-value): 6p22 (rs12526480,
LRRC16A, pβ=β9.1Γ10β9), 7q11
(rs13236689, CD36, pβ=β2.8Γ10β9),
10q21 (rs7896518, JMJD1C,
pβ=β2.3Γ10β12), 11q13 (rs477895,
BAD, pβ=β4.9Γ10β8), and 20q13
(rs151361, SLMO2, pβ=β9.4Γ10β9).
Three of these loci (10q21, 11q13, and 20q13) were replicated in European
Americans (Nβ=β14,909) and one (11q13) in Hispanic
Americans (Nβ=β3,462). For MPV
(Nβ=β4,531), genetic variants in 3 regions were significant
at p<5Γ10β8, two of which were also associated with
platelet count. Previously reported regions that were also significant in this
study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22,
17q11, and 19p13 for MPV. The most significant SNP in 1 region was also
associated with ADP-induced maximal platelet aggregation in whole blood (12q24).
Thus through a meta-analysis of GWAS enrolling African Americans, we have
identified 5 novel regions associated with platelet count of which 3 were
replicated in other ethnic groups. In addition, we also found one region
associated with platelet aggregation that may play a potential role in
atherothrombosis
Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis
Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong inΒ vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits
Outcomes in Childhood AML in the Absence of Transplantation in First Remission - Children\u27s Cancer Group (Ccg) Studies 2891 and Ccg 213
Background. The majority of childhood acute myeloid leukemia (AML) patients lack a matched-related bone marrow transplant (BMT) donor in first remission. Procedure. Disease-free survival (DFS), overall survival (OS), relapse-free survival (RFS), and post-relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent-to-treat, ITT) or who received (as-treated, AT) only chemotherapy intensification. Results. Outcomes at 8 years post-induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients \u3e3 years of age (P β€ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15-2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 \u3e12 months portends a much better OS for patients who relapse. Post-relapse treatment included BMT in 47% of patients. Conclusions. OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post-relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race
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