Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the ...International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.
In addition to its search for extrasolar planets, the NASA Kepler mission provides exquisite data on stellar oscillations. We report the detections of oscillations in 500 solar-type stars in the ...Kepler field of view, an ensemble that is large enough to allow statistical studies of intrinsic stellar properties (such as mass, radius, and age) and to test theories of stellar evolution. We find that the distribution of observed masses of these stars shows intriguing differences to predictions from models of synthetic stellar populations in the Galaxy.
We have analyzed solar-like oscillations in ~1700 stars observed by the Kepler Mission, spanning from the main sequence to the red clump. Using evolutionary models, we test asteroseismic scaling ...relations for the frequency of maximum power ( Delta *nmax), the large frequency separation ( Delta *D Delta *n), and oscillation amplitudes. We show that the difference of the Delta *D Delta *n- Delta *nmax relation for unevolved and evolved stars can be explained by different distributions in effective temperature and stellar mass, in agreement with what is expected from scaling relations. For oscillation amplitudes, we show that neither (L/M) s scaling nor the revised scaling relation by Kjeldsen & Bedding is accurate for red-giant stars, and demonstrate that a revised scaling relation with a separate luminosity-mass dependence can be used to calculate amplitudes from the main sequence to red giants to a precision of ~25%. The residuals show an offset particularly for unevolved stars, suggesting that an additional physical dependency is necessary to fully reproduce the observed amplitudes. We investigate correlations between amplitudes and stellar activity, and find evidence that the effect of amplitude suppression is most pronounced for subgiant stars. Finally, we test the location of the cool edge of the instability strip in the Hertzsprung-Russell diagram using solar-like oscillations and find the detections in the hottest stars compatible with a domain of hybrid stochastically excited and opacity driven pulsation.
Quantifying soil organic carbon (SOC) decomposition under warming is critical to predict carbon–climate feedbacks. According to the substrate regulating principle, SOC decomposition would decrease as ...labile SOC declines under field warming, but observations of SOC decomposition under warming do not always support this prediction. This discrepancy could result from varying changes in SOC components and soil microbial communities under warming. This study aimed to determine the decomposition of SOC components with different turnover times after subjected to long‐term field warming and/or root exclusion to limit C input, and to test whether SOC decomposition is driven by substrate lability under warming. Taking advantage of a 12‐year field warming experiment in a prairie, we assessed the decomposition of SOC components by incubating soils from control and warmed plots, with and without root exclusion for 3 years. We assayed SOC decomposition from these incubations by combining inverse modeling and microbial functional genes during decomposition with a metagenomic technique (GeoChip). The decomposition of SOC components with turnover times of years and decades, which contributed to 95% of total cumulative CO2 respiration, was greater in soils from warmed plots. But the decomposition of labile SOC was similar in warmed plots compared to the control. The diversity of C‐degradation microbial genes generally declined with time during the incubation in all treatments, suggesting shifts of microbial functional groups as substrate composition was changing. Compared to the control, soils from warmed plots showed significant increase in the signal intensities of microbial genes involved in degrading complex organic compounds, implying enhanced potential abilities of microbial catabolism. These are likely responsible for accelerated decomposition of SOC components with slow turnover rates. Overall, the shifted microbial community induced by long‐term warming accelerates the decomposition of SOC components with slow turnover rates and thus amplify the positive feedback to climate change.
The decomposition of SOC components with turnover times of years and decades, which contributed to 95% of total cumulative CO2 respiration, was greater in soils from warmed plots compared to the control. But the decomposition of labile SOC was similar in warmed plots compared to the control. The diversity of C‐degradation microbial genes generally declined with time during the incubation in all the soils from control and warmed plots, with and without root exclusion. Meanwhile, compared to the control, soils from warmed plots showed significant increase in the signal intensities of microbial genes involved in degrading complex organic compounds, implying enhanced potential abilities of microbial catabolism. Taken together, this study highlights changes in soil microbial community functions induced by long‐term warming. The shifted microbial community accelerates the decomposition of SOC components with slow turnover rates and thus amplify the positive feedback to climate change.
We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent ...were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.
Abstract
Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either
JAK2
or Calreticulin (
...CALR
) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First,
CALR
mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous
CALR
mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
Abstract
Soil microbial respiration is an important source of uncertainty in projecting future climate and carbon (C) cycle feedbacks. However, its feedbacks to climate warming and underlying ...microbial mechanisms are still poorly understood. Here we show that the temperature sensitivity of soil microbial respiration (
Q
10
) in a temperate grassland ecosystem persistently decreases by 12.0 ± 3.7% across 7 years of warming. Also, the shifts of microbial communities play critical roles in regulating thermal adaptation of soil respiration. Incorporating microbial functional gene abundance data into a microbially-enabled ecosystem model significantly improves the modeling performance of soil microbial respiration by 5–19%, and reduces model parametric uncertainty by 55–71%. In addition, modeling analyses show that the microbial thermal adaptation can lead to considerably less heterotrophic respiration (11.6 ± 7.5%), and hence less soil C loss. If such microbially mediated dampening effects occur generally across different spatial and temporal scales, the potential positive feedback of soil microbial respiration in response to climate warming may be less than previously predicted.
Background: Despite significant progress made in reducing dust exposures in underground coal miners in the United States, severe cases of coal workers’ pneumoconiosis (CWP), including progressive ...massive fibrosis (PMF), continue to occur among coal miners. Aims: To identify US miners with rapidly progressive CWP and to describe their geographic distribution and associated risk factors. Methods: Radiographic evidence of disease progression was evaluated for underground coal miners examined through US federal chest radiograph surveillance programmes from 1996 to 2002. A case of rapidly progressive CWP was defined as the development of PMF and/or an increase in small opacity profusion greater than one subcategory over five years. County based prevalences were derived for both CWP and rapidly progressive cases. Results: A total of 886 cases of CWP were identified among 29 521 miners examined from 1996 to 2002. Among the subset of 783 miners with CWP for whom progression could be evaluated, 277 (35.4%) were cases of rapidly progressive CWP, including 41 with PMF. Miners with rapidly progressive CWP were younger than miners without rapid progression, were more likely to have worked in smaller mines (<50 employees), and also reported longer mean tenure in jobs involving work at the face of the mine (in contrast to other underground mining jobs), but did not differ with respect to mean underground tenure. There was a clear tendency for the proportion of cases of rapidly progressive CWP to be higher in eastern Kentucky, and western Virginia. Conclusions: Cases of rapidly progressive CWP can be regarded as sentinel health events, indicating inadequate prevention measures in specific regions. Such events should prompt investigations to identify causal factors and initiate appropriate additional measures to prevent further disease.
Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation ...as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplantation at which survival differed.
We studied the effect of patients' age, adjusting for other significant factors affecting outcomes, in 1307 patients with severe aplastic anemia after HLA-matched sibling transplantation using logistic and Cox regression analysis. Age categories (<20 years, 20-40 years, >40 years) were determined using Martingale residual plots for overall survival and categories based on differences in survival.
Patients aged over 40 years old were more likely to have had immunosuppressive therapy, a poor performance score and a longer interval between diagnosis and transplantation. Neutrophil recovery was similar in all age groups but patients aged over 40 years had a lower likelihood of platelet recovery compared to patients aged less than 20 years (OR 0.45, P=0.01) but not compared to those aged 20-40 years (OR 0.60, P=0.10). Compared to the risk of mortality in patients aged less than 20 years, mortality risks were higher in patients over 40 years old (RR 2.70, P<0.0001) and in those aged 20-40 years (RR 1.69, P<0.0001). The mortality risk was also higher in patients aged over 40 years than in those 20-40 years old (RR 1.60, P=0.008).
Mortality risks increased with age. Risks were also higher in patients with a poor performance score and when the interval between diagnosis and transplantation was longer than 3 months, implying earlier referral would be appropriate when this treatment option is being considered.
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