Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity.
ASNase (
) substitution was approved in 2011 for ...allergic reactions.
has, however, been intermittently unavailable because of drug supply issues. The impact of
substitution or complete ASNase discontinuation is unknown.
Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute NCI standard risk SR: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to
but receiving all doses versus not receiving all ASNase doses.
We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio HR, 1.5; 95% CI, 1.2 to 1.9;
= .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with
substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6;
= .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6;
= .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7;
= .03).
Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of
shortages.
Understanding trophic cascades in terrestrial wildlife communities is a major challenge because these systems are difficult to sample properly. We show how a tradition of non‐random sampling has ...confounded this understanding in a textbook system (Yellowstone National Park) where carnivore Canis lupus (wolf) recovery is associated with a trophic cascade involving changes in herbivore Cervus canadensis (elk) behaviour and density that promote plant regeneration. Long‐term data indicate a practice of sampling only the tallest young plants overestimated regeneration of overstory aspen (Populus tremuloides) by a factor of 4–7 compared to random sampling because it favoured plants taller than the preferred browsing height of elk and overlooked non‐regenerating aspen stands. Random sampling described a trophic cascade, but it was weaker than the one that non‐random sampling described. Our findings highlight the critical importance of basic sampling principles (e.g. randomisation) for achieving an accurate understanding of trophic cascades in terrestrial wildlife systems.
Understanding trophic cascades in terrestrial wildlife communities is a major challenge because these systems are difficult to sample properly. We show how a tradition of non‐random sampling has confounded this understanding in a textbook system (Yellowstone National Park) where carnivore Canis lupus (wolf) recovery is associated with a trophic cascade involving changes in herbivore Cervus canadensis (elk) behaviour and density that promote plant regeneration.
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor ...2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.
Although sampling the five tallest young aspen in a stand is useful for detecting the occurrence of any aspen recruitment, this technique overestimates the population response of aspen to wolf ...reintroduction. Our original conclusion that random sampling described a trophic cascade that was weaker than the one described by non‐random sampling is unchanged.
Although sampling the five tallest young aspen in a stand is useful for detecting the occurrence of any aspen recruitment, this technique overestimates the population response of aspen to wolf reintroduction. Our original conclusion that random sampling described a trophic cascade that was weaker than the one described by non‐random sampling is unchanged.
Autism spectrum disorder (ASD) is one of the most prevalent and highly heritable neurodevelopmental disorders in humans. There is significant evidence that the onset and severity of ASD is governed ...in part by complex genetic mechanisms affecting the normal development of the brain. To date, a number of genes have been associated with ASD. However, the temporal and spatial co-expression of these genes in the brain remain unclear. To address this issue, we examined the co-expression network of 26 autism genes from AutDB (http://mindspec.org/autdb.html), in the framework of 3,041 genes whose expression energies have the highest correlation between the coronal and sagittal images from the Allen Mouse Brain Atlas database (http://mouse.brain-map.org). These data were derived from in situ hybridization experiments conducted on male, 56-day old C57BL/6J mice co-registered to the Allen Reference Atlas, and were used to generate a normalized co-expression matrix indicating the cosine similarity between expression vectors of genes in this database. The network formed by the autism-associated genes showed a higher degree of co-expression connectivity than seen for the other genes in this dataset (Kolmogorov-Smirnov P = 5×10⁻²⁸). Using Monte Carlo simulations, we identified two cliques of co-expressed genes that were significantly enriched with autism genes (A Bonferroni corrected P<0.05). Genes in both these cliques were significantly over-expressed in the cerebellar cortex (P = 1×10⁻⁵) suggesting possible implication of this brain region in autism. In conclusion, our study provides a detailed profiling of co-expression patterns of autism genes in the mouse brain, and suggests specific brain regions and new candidate genes that could be involved in autism etiology.
Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children's Oncology Group study AALL0232 ...tested two interventions to improve survival.
Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1.
Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis.
High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older.
A novel 2 : 1 host-guest complex forms between 8-
-butyl-6
-azapenta-benzo
,
,
,
,
corannulene (1) and C
with positive cooperativity (
= 2.56) and high affinity (
×
= 2.8 × 10
M
) at 25 °C. The C
...undergoes increasing shape complementarity toward 1 throughout the binding process.
Internalized homonegativity (IH) is widely recognized to negatively influence the health of lesbian, gay, bisexual, and queer/questioning (LGBQ +) individuals. It is not clear, however, the role that ...religiousness may play in the relationship between IH and health or how differing conceptualizations of IH or health may influence this relationship. We conducted a multi-level meta-analysis of 151 effect sizes from 68 studies to examine the relationship between IH and health as well as what may moderate this relationship. Results suggested that IH was consistently and negatively related to health (
r
= − .28). Analyses suggest that IH was most strongly related to mental health and well-being, evidencing a relatively weaker (though still negative) relationship with physical or sexual health. Analyses of different ways to measure IH suggest that scales that conceptualize IH to include distress (e.g., the Internalized Homonegativity Inventory) report stronger relationships with health than scales that conceptualize IH orthogonally from distress (e.g., the Internalized Homonegativity scale of the Lesbian, Gay, Bisexual Identity Salience Scale LGBIS). We failed to find significant moderation effects for religiousness, though it was hard to evaluate this relationship due to the poor quality of most measures of religiousness. We encourage researchers to use measures of IH that conceptualize IH orthogonally from distress (e.g., the LGBIS) and to use more nuanced measures of religiousness (e.g., religious belief, religious activity). We also encourage researchers to focus on how IH impacts less-often studied measures of health (e.g., physical health, suicidality).
To investigate the extent and causes of recent quaking aspen (
Populus tremuloides
) recruitment in northern Yellowstone National Park, we measured browsing intensity and height of young aspen in 87 ...randomly selected aspen stands in 2012, and compared our results to similar data collected in 1997-1998. We also examined the relationship between aspen recovery and the distribution of Rocky Mountain elk (
Cervus elaphus
) and bison (
Bison bison
) on the Yellowstone northern ungulate winter range, using ungulate fecal pile densities and annual elk count data. In 1998, 90% of young aspen were browsed and none were taller than 200 cm, the height at which aspen begin to escape from elk browsing. In 2012, only 37% in the east and 63% in the west portions of the winter range were browsed, and 65% of stands in the east had young aspen taller than 200 cm. Heights of young aspen were inversely related to browsing intensity, with the least browsing and greatest heights in the eastern portion of the range, corresponding with recent changes in elk density and distribution. In contrast with historical elk distribution (1930s-1990s), the greatest densities of elk recently (2006-2012) have been north of the park boundary (~5 elk/km
2
), and in the western part of the range (2-4 elk/km
2
), with relatively few elk in the eastern portion of the range (<2 elk/km
2
), even in mild winters. This redistribution of elk and decrease in density inside the park, and overall reduction in elk numbers, explain why many aspen stands have begun to recover. Increased predation pressure following the reintroduction of gray wolves (
Canis lupus
) in 1995-1996 played a role in these changing elk population dynamics, interacting with other influences including increased predation by bears (
Ursus
spp.), competition with an expanding bison population, and shifting patterns of human land use and hunting outside the park. The resulting new aspen recruitment is evidence of a landscape-scale trophic cascade in which a resurgent large carnivore community, combined with other ecological changes, has benefited aspen through effects on ungulate prey.
Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in ...subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.
•MRD measured by flow cytometry is prognostic in childhood B-ALL even with more effective high-dose methotrexate therapy.•Intensive therapy in MRD-positive patients altered the timing of relapse but did not overcome the poor prognostic significance of MRD.
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