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"Mack, D"
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Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia
Minimal/measurable residual disease (MRD) in Acute Myeloid Leukemia (AML) is defined as persistent leukemic cells below cytomorphological detection threshold. Next generation sequencing (NGS) of circulating cell-free DNA (cfDNA) to profile cancer-associated mutations has been shown to allow for quantification of disease burden in solid tumors and has also been suggested to enable minimally invasive follow-up of AML patients. In this pilot study we investigated the technical sensitivity and potential prognostic implications of cfDNA-based MRD monitoring in AML after allogeneic stem cell transplantation in comparison to donor chimerism analysis or, respectively, after consolidation chemotherapy. 75 cfDNA samples from 29 patients were analyzed by targeted NGS using a commercially available 10- or 37-gene hotspot panel (VariantPlex Core AML or Core Myeloid panel, ArcherDx). Patients’ leukemias exhibited 1–7 mutations as determined by routine diagnostics. Only previously identified mutations were considered for MRD evaluation. cfDNA was isolated in sufficient amounts for NGS from all samples (total yield 24 ng–5.2 µg). The sensitivity of variant detection increased with higher overall read count and higher mutation-specific coverage (variant allele frequency [VAF] range 0.08–100%). At least one previously known mutation was identified in 32/55 samples (58%, VAF 0.08–78.04%) which were taken during hematological complete remission (CR) in both patients after allogeneic stem cell transplantation (aHSCT) and patients after consolidation chemotherapy. In patients after aHSCT (
n
= 25), at least one previously known mutation was detected in 16/29 cfDNA samples (55.1%, VAF 0.08–6.7%) obtained when donor chimerism was ≥ 90% and in 6/6 samples (100%, VAF: 0.88–63.77%) with reduced donor chimerism. Probability of progression-free survival 17 months after aHSCT in patients with donor chimerism ≥ 90% but mutation-positive cfDNA was 64% compared to 100% in patients with undetectable MRD. In patients after consolidation chemotherapy, cfDNA was positive in all samples taken during CR (
n
= 4; VAF 0.26–29.84%) and non-CR (
n
= 4; VAF 8.46–100%). Our results indicate that NGS of cfDNA is suitable for MRD monitoring in AML and offers higher sensitivity for detecting residual leukemic cells than chimerism analysis in patients after aHSCT. Further studies are needed to evaluate clinical relevance of MRD status as determined in cfDNA.
Journal Article
Teaching race in perilous times
\"Multidisciplinary anthology on teaching issues of race and racism in US college classrooms\"-- Provided by publisher.
BOOK
Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans
Background
In the nematode
Caenorhabditis elegans
, longevity in response to germline ablation, but not in response to reduced insulin/IGF1-like signaling, is strongly dependent on the conserved protein kinase minibrain-related kinase 1 (MBK-1). In humans, the MBK-1 ortholog DYRK1A is associated with a variety of disorders, most prominently with neurological defects observed in Down syndrome. To better understand
mbk-1
’s physiological roles and their dependence on genetic background, we analyzed the influence of
mbk-1
loss on the transcriptomes of wildtype and long-lived, germline-deficient or insulin-receptor defective,
C. elegans
strains by RNA-sequencing.
Results
mbk-1
loss elicited global changes in transcription that were less pronounced in insulin-receptor mutant than in germline-deficient or wildtype
C. elegans
. Irrespective of genetic background,
mbk-1
regulated genes were enriched for functions in biological processes related to organic acid metabolism and pathogen defense. qPCR-studies confirmed
mbk-1
dependent induction of all three
C. elegans
Δ9-fatty acid desaturases,
fat-5
,
fat-6
and
fat-7
, in wildtype, germline-deficient and insulin-receptor mutant strains. Conversely,
mbk-1
dependent expression patterns of selected pathogen resistance genes, including
asp-12
,
dod-24
and
drd-50
, differed across the genetic backgrounds examined. Finally,
cth-1
and
cysl-2
, two genes which connect pathogen resistance to the metabolism of the gaseous messenger and lifespan regulator hydrogen sulfide (H
2
S), were commonly suppressed by
mbk-1
loss only in wildtype and germline-deficient, but not in insulin-receptor mutant
C. elegans
.
Conclusion
Our work reveals previously unknown roles of
C. elegans mbk-1
in the regulation of fatty acid desaturase- and H
2
S metabolic-genes. These roles are only partially dependent on genetic background. Considering the particular importance of fatty acid desaturation and H
2
S for longevity of germline-deficient
C. elegans
, we propose that these processes at least in part account for the previous observation that
mbk-1
preferentially regulates lifespan in these worms.
Journal Article
Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data
Objective:Health administrative databases can be used to track chronic diseases. The aim of this study was to validate a case ascertainment definition of paediatric-onset inflammatory bowel disease (IBD) using administrative data and describe its epidemiology in Ontario, Canada.Methods:A population-based clinical database of patients with IBD aged <15 years was used to define cases, and patient information was linked to health administrative data to compare the accuracy of various patterns of healthcare use. The most accurate algorithm was validated with chart data of children aged <18 years from 12 medical practices. Administrative data from the period 1991–2008 were used to describe the incidence and prevalence of IBD in Ontario children. Changes in incidence were tested using Poisson regression.Results:Accurate identification of children with IBD required four physician contacts or two hospitalisations (with International Classification of Disease (ICD) codes for IBD) within 3 years if they underwent colonoscopy and seven contacts or three hospitalisations within 3 years in those without colonoscopy (children <12 years old, sensitivity 90.5%, specificity >99.9%; children <15 years old, sensitivity 89.6%, specificity >99.9%; children <18 years old, sensitivity 91.1%, specificity 99.5%). Age- and sex-standardised prevalence per 100 000 population of paediatric IBD has increased from 42.1 (in 1994) to 56.3 (in 2005). Incidence per 100 000 has increased from 9.5 (in 1994) to 11.4 (in 2005). Statistically significant increases in incidence were noted in 0–4 year olds (5.0%/year, p = 0.03) and 5–9 year olds (7.6%/year, p<0.0001), but not in 10–14 or 15–17 year olds.Conclusion:Ontario has one of the highest rates of childhood-onset IBD in the world, and there is an accelerated increase in incidence in younger children.
Journal Article
Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro
Background: Mucins are large complex glycoproteins that protect intestinal mucosal surfaces by limiting access of environmental matter to their epithelial cells. Several mucin genes have been described, including MUC3 that is a membrane associated mucin of the small intestine. Increased MUC3 mRNA transcription is induced by incubation of intestinal epithelial cells with a Lactobacillus strain known to be adherent to them. Aims: To determine whether increased epithelial cell MUC3 mucin expression in response to Lactobacillus strains results in increased extracellular secretion of MUC3 mucins and the importance of epithelial cell adherence in modulation of MUC3 mucin expression. Methods: HT29 cells grown to enhance expression of MUC3 mucins were incubated with selected Lactobacillus strains. Spent cell culture medium was collected for detection of secreted MUC3 mucins using dot blot immunoassay with a generated MUC3 antibody. Post-incubation HT29 cell RNA was collected for analysis of MUC3 expression by northern blot analysis using a MUC3 cDNA probe. In vitro binding studies using Lactobacillus strains incubated alone or coincubated with enteropathogenic Escherichia coli strain E2348/69 were used for adherence and inhibition of adherence studies, respectively. Results:Lactobacillus strains with minimal ability to adhere to HT29 cells failed to induce upregulation of mucin gene expression. There was a direct correlation between upregulation of MUC3 mucin mRNA expression and extracellular secretion of MUC3 mucin. The same Lactobacillus strains that increased extracellular secretion of MUC3 mucin led to reduced adherence of enteropathogen E coli E2348/69 during coincubation experiments. Conclusion: Probiotic microbes induce MUC3 mucin transcription and translation with extracellular secretion of the MUC3 mucins. Epithelial cell adherence enhances the effects of probiotics on eukaryotic mucin expression.
Journal Article
A Meta-Analysis of Social Skills Interventions for Preschoolers with or at Risk of Early Emotional and Behavioral Problems
Early social–behavioral intervention that emphasizes social skill training is critical to addressing emotional and behavioral problems in early childhood. In this meta-analysis review, we examined all the social skills intervention studies for preschoolers with, or at risk of, emotional and behavioral problems using group designs. This review included 25 studies that met the inclusion criteria. The robust variance estimation method was used to calculate the overall effect size of all the included studies, as this method can count for the pre-existing difference between the experiment and control groups. The included studies yielded an overall effect of 0.54 from the 151 effect sizes that were obtained for the 3484 preschool participants. Curriculum, integration, and treatment fidelity were identified as significant moderators of effects.
Journal Article
Comparison of Laboratory and On-Field Performance of American Football Helmets
The relationship between laboratory and on-field performance of football helmets was assessed for 31 football helmet models selected from those worn by players in the 2015–2019 National Football League (NFL) seasons. Linear impactor tests were conducted with helmets placed on an instrumented Hybrid III head and neck assembly mounted on a sliding table. Based on impacts to each helmet at six impact locations and three velocities, a helmet performance score (HPS) was calculated using a linear combination of the head injury criterion (HIC) and the diffuse axonal multi-axis general evaluation (DAMAGE). To determine the on-field performance of helmets, helmet model usage, player participation, and incident concussion data were collected from the five NFL seasons and used to calculate helmet model-specific concussion rates. Comparison of laboratory HPS to the helmet model-specific concussion rates on a per play basis showed a positive correlation (r2 = 0.61, p < 0.001) between laboratory and on-field performance of helmet models, indicating that helmets which exhibited reduced impact severity in the laboratory tests were also generally associated with lower concussion rates on-field. Further analysis showed that NFL-prohibited helmet models exhibited a significantly higher odds of concussion (OR 1.24; 95% CI 1.04–1.47; p = 0.017) relative to other helmet models.
Journal Article
Physical activity and subjective well-being among people with spinal cord injury: a meta-analysis
Study design:
Meta-analysis of cross-sectional, quasi-experimental and experimental studies.
Objective:
To determine if there is an association between physical activity (PA) and subjective well-being (SWB) among people living with spinal cord injury (SCI).
Methods:
Literature searches were conducted using multiple databases (Embase, CINAHL, Medline, PsychINFO and SPORTDiscus) to identify studies involving people with SCI that included a measure of PA and at least one measure of SWB (for example, symptoms of depression, life satisfaction, mood). Relevant data were extracted from the studies and subjected to meta-analysis.
Results:
A total of 21 studies were retrieved yielding 78 effect sizes and a total sample size of 2354. Overall, there were statistically significant, small- to medium-sized effects for the relationships between PA and SWB (broadly defined), PA and depressive symptoms, and PA and life satisfaction. Studies using experimental and quasi-experimental designs yielded larger effects for SWB (broadly defined) and life satisfaction, than studies using nonexperimental study designs.
Conclusions:
There is a small- to medium-sized positive relationship between PA and SWB among people with SCI that holds across a wide range of measures and operational definitions of these constructs.
Journal Article
Mating-responsive genes in reproductive tissues of female Drosophila melanogaster
Male-derived accessory gland proteins that are transferred to females during mating have profound effects on female reproductive physiology including increased ovulation, mating inhibition, and effects on sperm utilization and storage. The extreme rates of evolution seen in accessory gland proteins may be driven by sperm competition and sexual conflict, processes that may ultimately drive complex interactions between female- and male-derived molecules and sperm. However, little is known of how gene expression in female reproductive tissues changes in response to the presence of male molecules and sperm. To characterize this response, we conducted parallel genomic and proteomic analyses of gene expression in the reproductive tract of 3-day-old unmated and mated female Drosophila melanogaster. Using DNA microarrays, we identified 539 transcripts that are differentially expressed in unmated vs. mated females and revealed a striking peak in differential expression at 6 h postmating and a marked shift from primarily down-regulated to primarily up-regulated transcripts within 3 h after mating. Combining two-dimensional gel electrophoresis and liquid chromatography mass spectrometry analyses, we identified 84 differentially expressed proteins at 3 h postmating, including proteins that appeared to undergo posttranslational modification. Together, our observations define transcriptional and translational response to mating within the female reproductive tract and suggest a bimodal model of postmating gene expression initially correlated with mating and the final stages of female reproductive tract maturation and later with the declining presence of male reproductive molecules and with sperm maintenance and utilization.
Journal Article