Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform ...an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Several different investigators have reported increased stroke mortality in the southeastern United States, leading to the introduction of the term “Stroke Belt.” The results presented here from the ...Veterans Administration Hypertension Screening and Treatment Program (HSTP) demonstrate an increased all-cause mortality among hypertensive patients seen in HSTP clinics in the southeastern United States when compared with similar patients from other HSTP clinics. Several different groupings of southeastern states were examined and compared with nine states west of the Mississippi River. A total of 11 936 male veterans, 5737 of whom were black, were identified as hypertensive during 1974-1976 in 32 HSTP clinics. Their mean age was 52.4±10.4 years, and their mean pretreatment blood pressure was 153.8±19.1/100.4±9.8 mm Hg. During a minimum of 13.9 years of followup, 5360 (44.9%) of these patients died. Proportional hazards modeling was used to fit a basic survival model with terms representing race, age, blood pressure, smoking, and obesity. Risk was increased with higher blood pressure, age, and smoking and with lower body mass index. For 6 HSTP clinics in an 11-state Stroke Belt (defined as states with stroke mortality >10% above the United States average), the relative risk of death was 1.226 (95% confidence interval, 1.106-1.358) when compared with 9 states west of the Mississippi River. For two different groupings of southeastern states with 10 and 8 HSTP clinics the relative risk of death was 1.231 and 1.295. Mean martingale residuals were used to indicate the relative risk at each clinic after applying statistical controls for age, race, blood pressure, smoking, and body mass index. Four of the 6 Stroke Belt clinics had positive means, indicating that there was excess all-cause mortality among the patients of those clinics. In contrast, only 2 of the 10 non-Stroke Belt clinics had positive means.
Background: Loss of genetic heterogeneity (allelic loss or loss of heterozygosity) on chromosome arm 8p is frequent in squamous cell carcinomas of the head and neck and has been associated with poor ...prognosis. We have previously demonstrated that there are three minimal regions of allelic loss on this chromosome arm. The location of each region is marked by a microsatellite locus: D8S264 (8p23), D8S552 (8p23-p22), and D8S133 (8p21). These findings imply the existence of at least three putative tumor suppressor genes on this chromosome arm that may become inactivated during the progression of squamous cell carcinoma. Purpose: We used allelic loss data from these three loci to determine if inactivation of these putative suppressors is associated with poor prognosis for patients with squamous cell carcinoma of the supraglottic larynx. We also used multivariate statistics to compare the prognostic power of allelic loss at these genetic markers with that of demographic, clinical, and histopathologic parameters. Methods: We examined the D8S264, D8S552, and D8S133 microsatellites in tumors from a retrospective population of 59 patients. All patients had histologically confirmed squamous cell carcinoma of the supraglottic larynx and had been treated surgically. DNA was extracted from matched sets of normal and microdissected tumor tissue and used for polymerase chain reaction amplification of the microsatellite markers. Reaction products were separated by denaturing gel electrophoresis and visualized by autoradiography. Patient data were obtained from the original pathology report and from the tumor registry of the Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO. Histo-pathologic data were obtained by reviewing the portion of the resection specimen used for DNA extraction. Parameters whose association with reduced disease-free interval and reduced disease-specific survival was statistically significant were identified by use of the Kaplan—Meier method and the logrank statistic. Multivariate Cox proportional hazards models were used to identify independent predictors of poor prognosis. All statistical tests were two-sided. Results: In this patient population, allelic loss at the D8S264 locus was associated with both shorter disease-free interval (logrank P =.028) and reduced disease-specific survival (logrank P =.004). Allelic loss at the next most centromeric locus, D8S552, had a statistically significant association with only reduced disease-specific survival (logrank P =.034), whereas allelic loss at the most centromeric region, D8S133, showed no statistically significant association with reductions in either interval. Multivariate Cox models suggested that D8S264 was the only 8p marker of the three microsatellites with a statistically significant and independent association with shortened disease-free interval (relative risk RR = 3.38; P =.0107) and reduced disease-specific survival (RR = 3.41; P =.0105). Conclusions: Allelic loss in the p23 region of chromosome 8 appears to be a statistically significant, independent predictor of poor prognosis in patients with supraglottic squamous cell carcinoma.
Cytogenetic analysis of acute myeloid leukemia (AML) cells has accelerated the identification of genes important for AML pathogenesis. To complement cytogenetic studies and to identify genes altered ...in AML genomes, we performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using 1.85 million feature SNP arrays. Acquired copy number alterations (CNAs) were confirmed using an ultra-dense array comparative genomic hybridization platform. A total of 201 somatic CNAs were found in the 86 AML genomes (mean, 2.34 CNAs per genome), with French-American-British system M6 and M7 genomes containing the most changes (10-29 CNAs per genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, whereas 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several CNA regions were recurrent. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls occurred in samples with a normal karyotype. Collectively, 34 of 86 AML genomes (40%) contained alterations not found with cytogenetics, and 98% of these regions contained genes. Of 86 genomes, 43 (50%) had no CNA or UPD at this level of resolution. In this study of 86 adult AML genomes, the use of an unbiased high-resolution genomic screen identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumor suppressor genes.
...the mechanism of AZM's anti-inflammatory effects may have reflected direct effects on the immune response, or an indirect effect through antibacterial actions of AZM leading to alteration in ...bacteria abundance and a reduction in neutrophilic inflammation. ...it remains imperative to investigate whether the potential beneficial effects of AZM for the prevention of post-RSV wheezing are related, at least in part, to its antibacterial effects. Characteristic All participants AZM group (n = 19) Placebo group (n = 20) Age at enrollment (mo)low * 3.8 ± 2.9 3.7 ± 3.7 3.9 ± 2.0 Sex: Male 59.0% 47.4% 70.0% Race White 64.1% 63.2% 65.0% Black 35.9% 36.8% 35% Birth weight (kg)low * 3.4 ± 0.5 3.3 ± 0.6 3.4 ± 0.4 Length of pregnancy (wk)low * 38.8 ± 1.4 38.9 ± 1.3 38.7 ± 1.4 Maternal smoking during pregnancy 7.7% 10.5% 5.0% History of breast-feeding 28.2% 31.6% 25.0% Tobacco smoke exposure 35.9% 42.1% 30% Pet exposure 61.5% 63.1% 60.0% History of eczema 17.9% 21.1% 15.0% Parental history of asthma 41.0% 42.1% 40.0% Duration of respiratory symptoms before randomization (d)low * 5.4 ± 1.4 5.2 ± 1.3 5.5 ± 1.4 Duration of hospitalization (h)low * 63.4 ± 53.2 58.0 ± 41.4 68.5 ± 63.2 Lowest O2 saturation on room airlow * 90.8 ± 4.3 91.4 ± 4.9 90.3 ± 3.6 Table I Baseline characteristics of the APW-RSV study participants Data are expressed as proportion of children in each group except as noted.
DNMT3A Mutations in Acute Myeloid Leukemia Ley, Timothy J; Ding, Li; Walter, Matthew J ...
The New England journal of medicine,
12/2010, Letnik:
363, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Whole-genome sequence analysis of cells from a patient with acute myeloid leukemia (AML) revealed a mutation in DNMT3A, which encodes an enzyme that methylates DNA. Subsequent analyses showed that ...DNMT3A was mutated in 33.7% of patients with AML with an intermediate-risk cytogenetic profile.
Whole-genome sequencing is an unbiased approach for discovering somatic variations in cancer genomes. We recently reported the DNA sequence and analysis of the genomes of two patients with acute myeloid leukemia (AML) with a normal karyotype.
1
,
2
We did not find new recurring mutations in the first study but did observe a recurrent mutation in
IDH1,
encoding isocitrate dehydrogenase 1, in the second study.
2
Subsequent work has confirmed and extended this finding, showing that mutations in
IDH1
and related gene
IDH2
are highly recurrent in patients with an intermediate-risk cytogenetic profile (20 to 30% frequency) and are associated with a . . .
Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two ...decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVES: In the absence of a validated "user-friendly" method of scoring asthma severity, the authors derived the pulmonary score (PS). The purpose of this study was to begin validation trials of ...the PS by comparing it with the peak expiratory flow rate (PEFR). METHODS: The study enrolled a convenience sample of children, aged 5-17 years, who came to the emergency department (ED) for treatment of an acute asthma exacerbation. The PEFR (best of three attempts) and the PS were measured before and after the first albuterol treatment by a physician and a nurse from a pool of 45 trained observers. The PS includes respiratory rate, wheezing, and retractions, each rated on a 0-3 scale. Decreasing PS and increasing PEFR indicate clinical improvement. Pre- and post-treatment PEFRs and PSs were compared using paired t-tests to establish construct validity. Correlation of pre- and post-treatment PSs with PEFRs was measured to establish criterion validity. RESULTS: Forty-six subjects completed the study. Mean percent predicted PEFR improved after treatment by 20.7% (p = 0.0001), and mean PS by 1.5 for nursing-obtained scores (p < 0.0001) and 1.9 for physician-obtained scores (p < 0.0001). Pre- and post-treatment PSs were significantly correlated with PEFRs. Correlations for the nursing-obtained scores were pre-treatment r = -0.57 (p = 0.0003) and post-treatment r = -0.67 (p = 0.0001), and for the physician-obtained scores were pre-treatment r = -0.44 (p = 0.003) and post-treatment r = -0.56 (p = 0.0001). The pre-treatment interrater reliability was 0.62 and the post-treatment was 0.53. CONCLUSIONS: These data support the construct and criterion validities of the PS as a measure of asthma severity among children in the ED. The PS is a practical substitute to estimate airway obstruction in children who are too young or too sick to obtain PEFRs.
This article presents the design of and some results from a new prospective mortality study of a national cohort of about 50,000 U.S. veterans who were diagnosed as hypertensive in the mid 1970s, ...based on approximately 21 yr of follow-up. This national cohort is male with an average age at recruitment of 51 ± 12 yr; 35% were black and 81% had been smokers at one time. Because the subjects have been receiving care at various U.S. Veterans Administration (VA) hospitals, access to and quality of medical care are relatively homogeneous. The health endpoints available for analysis include all-cause mortality and specific diagnoses for morbidity during VA hospitalizations; only the mortality results are discussed here. Nonpollution predictor variables in the baseline model include race, smoking (ever or at recruitment), age, systolic and diastolic blood pressure (BP), and body mass index (BMI). Interactions of BP and BMI with age were also considered. Although this study essentially controls for socioeconomic status by design because of the homogeneity of the cohort, selected ecological variables were also considered at the ZIP code and county levels, some of which were found to be significant predictors. Pollutants were averaged by year and county for TSP, PM10, CO, O3, and NO2; SO2 and Pb were considered less thoroughly. Both mean and peak levels were considered for gases. SO42 data from the AIRS database and PM2.5, coarse particles, PM15, and SO42 from the U.S. EPA Inhalable Particulate (IP) Network were also considered. Four relevant exposure periods were defined: 1974 and earlier (back to 1953 for TSP), 1975-1981, 1982-1988, and 1989-1996. Deaths during each of the three most recent exposure periods were considered separately, yielding up to 12 combinations of exposure and mortality periods for each pollutant. Associations between concurrent air quality and mortality periods were considered to relate to acute responses; delayed associations with prior exposures were considered to be emblematic of initiation of chronic disease. Preexposure mortality associations were considered to be indirect (noncausal). The implied mortality risks of long-term exposure to air pollution were found to be sensitive to the details of the regression model, the time period of exposure, the locations included, and the inclusion of ecological as well as personal variables. Both positive and negative statistically significant mortality responses were found. Fine particles as measured in the 1979-1984 U.S. EPA Inhalable Particulate Network indicated no significant (positive) excess mortality risk for this cohort in any of the models considered. Among the positive responses, indications of concurrent mortality risks were seen for NO2 and peak O3, with a similar indication of delayed risks only for NO2. The mean levels of these excess risks were in the range of 5-9%;. Peak O3 was dominant in two-pollutant models and there was some indication of a threshold in response. However, it is likely that standard errors of the regression coefficients may have been underestimated because of spatial autocorrelation among the model residuals. The significant variability of responses by period of death cohort suggests that aggregation over the entire period of follow-up obscures important aspects of the implied pollution-mortality relationships, such as early depletion of the available pool of those subjects who may be most susceptible to air pollution effects.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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