Proteomic analysis of childhood leukemia.

Childhood acute lymphoblastic and myeloid leukemias are stratified into molecular and cytogenetic subgroups important for prognosis and therapy. Studies have shown that gene expression profiles can discriminate between leukemia subtypes. Thus, proteome analysis similarly holds the potential for characterizing different subtypes of childhood leukemia. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze cell lysates from childhood leukemia cell lines as well as pretreatment leukemic bone marrow derived from childhood leukemia cases. Comparison of the acute myeloid leukemia (AML) cell line, Kasumi, and the biphenotypic myelomonocytic cell line, MV4;11, with the acute lymphoblastic leukemia (ALL) cell lines, 697 and REH, revealed many differentially expressed proteins. In particular, one 8.3 kDa protein has been identified as a C-terminal truncated ubiquitin. Analysis of childhood leukemia bone marrow showed differentially expressed proteins between AML and ALL, including a similar peak at 8.3 kDa, as well as several proteins that differentiate between the ALL t(12;21) and hyperdiploid subtypes. These results demonstrate the potential for proteome analysis to distinguish between various forms of childhood leukemia. Future analyses are warranted to validate these findings and to investigate the role of the C-terminal truncated ubiquitin in the etiology of ALL.     

Marital status as a predictor of survival in idiopathic dilated cardiomyopathy: The Washington,DC dilated cardiomyopathy study

Marital status and other socioeconomic and clinical factors were examined as predictors of survival in idiopathic dilated cardiomyopathy using data from a hospital-based study in Washington, DC. Twenty-five (18.1%) of the cases (n = 138) were single, 66 (47.8%) were married, 25 (18.1%) were divorced or separated, and 22 (15.9%) were widowed. Married patients were more likely to be male, to have an annual household income grater than $15,000, and to live with another person (p 0.01) as compared with those who were single, widowed, divorced or separated. Widowed patients were older on average and more likely to abstain from drinking alcohol. The cumulative survival among widowed patients at 12 and 24 months was 54.6 and 48.5%, respectively, as compared with 75.8 and 59.0% among single patients and 80.0 and 71.2% among married patients. The survival of divorced or separated patients was relatively good with a cumulative survival of 84.0% at both 12 and 24 months. Older age, lower ejection fraction, ventricular arrhythmias, bundle branch block, and marital status were significant predictors of survival in univariate analysis using the proportional hazards model. In multivariable analysis, age, race, ejection fraction, and marital status were statistically significant independent predictors of survival, with single patients with idiopathic dilated cardiomyopathy having a poorer survival than those who were married (adjusted RR = 2.5, 95% CI 1.1–6.2, p < 0.05). The observed association with marital status may be explained by psychosocial factors not examined in the present study such as quality of social network or psychological stress.Abbreviations IDCM idiopathic dilated cardiomyopathy - T4 thyroxine - TSH thyroid stimulating hormone     

Chronic respiratory illness as a predictor of survival in idiopathic dilated cardiomyopathy: the Washington, DC, Dilated Cardiomyopathy Study.

Although bronchial asthma and emphysema have been associated with idiopathic dilated cardiomyopathy in case-control studies, little is known about the prognostic importance of chronic respiratory disease in idiopathic dilated cardiomyopathy. To study this, we examined history of bronchial asthma, emphysema and chronic bronchitis, and respiratory medication use as possible predictors of survival in idiopathic dilated cardiomyopathy using data from a Washington, DC, population-based study (n = 129). The cumulative survival rates among patients with a history of emphysema or chronic bronchitis were 60% and 48% at 12 and 36 months, respectively, compared with 81.8% and 67.2% among patients without emphysema or chronic bronchitis. The survival rates of idiopathic dilated cardiomyopathy patients with and without a history of bronchial asthma at the time of idiopathic dilated cardiomyopathy diagnosis were similar. In multivariate analysis using the proportional hazards model, only ventricular arrhythmias and ejection fraction were found to be statistically significant predictors of survival in idiopathic dilated cardiomyopathy. The adjusted relative risk estimate for emphysema and chronic bronchitis was close to one. Thus, the results of this population-based study do not suggest that history of chronic respiratory illness is an independent predictor of survival in idiopathic dilated cardiomyopathy.     

Bacterial resistance of refrigerated and cryopreserved aortic allografts in an experimental virulent infection model

PURPOSE: The bacterial resistance of refrigerated and cryopreserved aortic allografts in a highly virulent infection in a dog model was studied. METHODS: The infrarenal aorta of 12 dogs was replaced with either a cryopreserved aortic allograft (group I, n = 6) or a refrigerated aortic allograft (group II, n = 6) in infected sites. Allografts were harvested from dogs and stored for 1 week, either by cryopreservation (-140 degrees C) or refrigerated method (4 degrees C), in a preservation medium. At the time of implantation, induction of infection was achieved with an infected piece of knitted Dacron placed just beneath the allograft. The Dacron was contaminated in vitro by soaking it in a solution with Staphylococcus aureus PR209. All 12 dogs received no adjunct antibiotic or antithrombotic therapy. Four weeks after implantation, the animals were killed to recover the grafts for bacteriological and histological analyses. Bacterial results were expressed as colony-forming units (CFU)/cm2 of graft material. RESULTS: In group I, only one allograft grew bacteria at 2. 16 x 10(6 )CFU/cm2, with a blood culture positive for S aureus. In group II, one dog died at 3 weeks from a false septic aneurysm rupture, all the allografts were infected (P <.05) with a mean bacterial count of 9.41 +/- 6.8 x 10(4) CFU/cm2, and three blood cultures were positive for S aureus. The patency of the grafts was analyzed at the time of recovery. Three laminar thrombi without occlusion were present in group I; none were present in group II. A better preserved endothelium in group I was revealed by means of histologic analysis staining with factor VIII antibody before implantation. After 4 weeks of implantation in the infected site, infected allografts presented polynuclear infiltrates in the media with a high degree of inflammatory reaction, and endothelial recovery was more significant in group I, with numerous young plump cells. CONCLUSION: This study demonstrates that cryopreserved allografts implanted in infected sites in a dog model can produce greater bacterial resistance.     

European genetic ancestry associated with risk of childhood ependymoma

BackgroundEpendymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.MethodsIn a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).ResultsCBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08–1.59, P_meta = 6.7 × 10⁻³). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45–2.73; P = 2.2 × 10⁻⁵) but which was not validated in an independent set of posterior fossa type A patients.ConclusionsInterethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.     

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.     

Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium

Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case–control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.     

Polycyclic Aromatic Hydrocarbons in Residential Dust: Sources of Variability

Background: There is interest in using residential dust to estimate human exposure to environmental contaminants.Objectives: We aimed to characterize the sources of variability for polycyclic aromatic hydrocarbons (PAHs) in residential dust and provide guidance for investigators who plan to use residential dust to assess exposure to PAHs.Methods: We collected repeat dust samples from 293 households in the Northern California Childhood Leukemia Study during two sampling rounds (from 2001 through 2007 and during 2010) using household vacuum cleaners, and measured 12 PAHs using gas chromatography–mass spectrometry. We used a random- and a mixed-effects model for each PAH to apportion observed variance into four components and to identify sources of variability.Results: Median concentrations for individual PAHs ranged from 10 to 190 ng/g of dust. For each PAH, total variance was apportioned into regional variability (1–9%), intraregional between-household variability (24–48%), within-household variability over time (41–57%), and within-sample analytical variability (2–33%). Regional differences in PAH dust levels were associated with estimated ambient air concentrations of PAH. Intraregional differences between households were associated with the residential construction date and the smoking habits of residents. For some PAHs, a decreasing time trend explained a modest fraction of the within-household variability; however, most of the within-household variability was unaccounted for by our mixed-effects models. Within-household differences between sampling rounds were largest when the interval between dust sample collections was at least 6 years in duration.Conclusions: Our findings indicate that it may be feasible to use residential dust for retrospective assessment of PAH exposures in studies of health effects.     

月经和生育因素对妇女肺癌危险度的影响

目的 验证雌激素可能对肺癌危险度产生的影响 方法 1994～1998年在甘肃省陇东地区进行了一项女性人群的病例对照研究,分析了月经和生育因素与肺癌危险度之间的关系。病例组为109例女性肺癌病例和435名女性为对照组,对照组是根据人口调查资料,按年龄和地区与病例频数匹配得到的。结果 初潮年龄晚(趋势检验P=0.015)、绝经年龄晚(趋势检验P=0.074)的女性,其肺癌比值比较低。结论 尽管有局限性,上述发现表明雌激素在女性肺癌病因学中起到一定作用。