Survival of Adults with Acute Lymphoblastic Leukemia in Germany and the United States

Background

Adulthood acute lymphoblastic leukemia (ALL) is a rare disease. In contrast to childhood ALL, survival for adults with ALL is poor. Recently, new protocols, including use of pediatric protocols in young adults, have improved survival in clinical trials. Here, we examine population level survival in Germany and the United States (US) to gain insight into the extent to which changes in clinical trials have translated into better survival on the population level.

Methods

Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients age 15–69 diagnosed with ALL were included. Period analysis was used to estimate 5-year relative survival (RS).

Results

Overall 5-year RS was estimated at 43.4% for Germany and 35.5% for the US (p = 0.004), with a decrease in survival with increasing age. Survival was higher in Germany than the US for men (43.6% versus 37.7%, p = 0.002) but not for women (42.4% versus 40.3%, p>0.1). Five-year RS estimates increased in Germany and the US between 2002 and 2006 by 11.8 and 7.3 percent units, respectively (p = 0.02 and 0.04, respectively).

Conclusions

Survival for adults with ALL continues to be low compared with that for children, but a substantial increase in 5-year survival estimates was seen from 2002 to 2006 in both Germany and the US. The reasons for the survival differences between both countries require clarification.     

Quantification of Protein Copy Number in Yeast: The NAD+ Metabolome

Saccharomyces cerevisiae is calorie-restricted by lowering glucose from 2% to 0.5%. Under low glucose conditions, replicative lifespan is extended in a manner that depends on the NAD⁺-dependent protein lysine deacetylase Sir2 and NAD⁺ salvage enzymes. Because NAD⁺ is required for glucose utilization and Sir2 function, it was postulated that glucose levels alter the levels of NAD⁺ metabolites that tune Sir2 function. Though NAD⁺ precursor vitamins, which increase the levels of all NAD⁺ metabolites, can extend yeast replicative lifespan, glucose restriction does not significantly change the levels or ratios of intracellular NAD⁺ metabolites. To test whether glucose restriction affects protein copy numbers, we developed a technology that combines the measurement of Urh1 specific activity and quantification of relative expression between Urh1 and any other protein. The technology was applied to obtain the protein copy numbers of enzymes involved in NAD⁺ metabolism in rich and synthetic yeast media. Our data indicated that Sir2 and Pnc1, two enzymes that sequentially convert NAD⁺ to nicotinamide and then to nicotinic acid, are up-regulated by glucose restriction in rich media, and that Pnc1 alone is up-regulated in synthetic media while levels of all other enzymes are unchanged. These data suggest that production or export of nicotinic acid might be a connection between NAD⁺ and calorie restriction-mediated lifespan extension in yeast.     

The disulfide catalyst QSOX1 maintains the colon mucosal barrier by regulating Golgi glycosyltransferases

Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide‐mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide‐mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.     

Stiffness of skinned rabbit psoas fibers in MgATP and MgPPi solution.

The stiffness of single skinned rabbit psoas fibers was measured during rapid length changes applied to one end of the fibers. Apparent fiber stiffness was taken as the initial slope when force was plotted vs. change in sarcomere length. In the presence of MgATP, apparent fiber stiffness increased with increasing speed of stretch. With the fastest possible stretches, the stiffness of relaxed fibers at an ionic strength of 20 mM reached more than 50% of the stiffness measured in rigor. However, it was not clear whether apparent fiber stiffness had reached a maximum, speed independent value. The same behavior was seen at several ionic strengths, with increasing ionic strength leading to a decrease in the apparent fiber stiffness measured at any speed of stretch. A speed dependence of apparent fiber stiffness was demonstrated even more clearly when stiffness was measured in the presence of 4 mM MgPPi. In this case, stiffness varied with speed of stretch over about four decades. This speed dependence of apparent fiber stiffness is likely due to cross-bridges detaching and reattaching during the stiffness measurement (Schoenberg, 1985. Biophys. J. 48:467). This means that obtaining an estimate of the maximum number of cross-bridges attached to actin in relaxed fibers at various ionic strengths is not straightforward.(ABSTRACT TRUNCATED AT 250 WORDS)     

An improved enzymatic synthesis of labeled gibberellin A12-aldehyde and gibberellin A12

The biochemical synthesis of labeled gibberellin A12-7-aldehyde (GA12ald) and and gibberellin A12 (GA12) from labeled R,S-mevalonic acid (MVA) using cell-free extracts from pumpkin (Cucurbita maxima) endosperm has been improved over the previously reported procedure. Three major improvements were developing a one-step HPLC procedure to isolate GA12ald and GA12 in radiochemically pure form; adjusting the pH of the reaction mix to pH 6.9 which increased the GA12ald/GA12 ratio over that at pH 7.8 by ca. 18-fold while reducing the combined yield of these two compounds by less than 17%; and developing a technique that permitted sampling of the fruits without interrupting growth; this doubled the fraction of extracts with "high activity." Conversion of MVA into GA12ald or GA12 displayed Michaelis-Menten kinetics with half-maximal synthesis at 0.4 mM MVA. Four-hour incubations afforded the highest yields from 0.25 mM MVA. Up to 15 and 7% of the MVA was incorporated into GA12ald and GA12, respectively. About one-quarter of the extracts incorporated at least 10% of the 0.25 mM MVA into GA12ald. One pumpkin fruit can provide sufficient endosperm to synthesize ca. 0.6 mumol of GA12ald.     

Impact of Uncertainties in Exposure Assessment on Thyroid Cancer Risk among Persons in Belarus Exposed as Children or Adolescents Due to the Chernobyl Accident

BackgroundThe excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of ¹³¹I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error.MethodsWe examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996–2004, who had direct thyroid ¹³¹I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied.ResultsThere was a statistically significant (p<0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy⁻ (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy⁻ (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy⁻ (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy⁻ (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053–0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2).ConclusionsIn summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.