Germline JAK1 gain-of-function mutations cause autosomal dominant immune dysregulation and hypereosinophilia with eosinophilic infiltration of the gastrointestinal tract, massive hepatosplenomegaly ...and severe atopic dermatitis that can be successfully treated with ruxolitinib, an oral JAK1/2 inhibitor.
Pediatric acute myeloid leukemia (pAML) is characterized by heterogeneous cellular composition, driver alterations and prognosis. Characterization of this heterogeneity and how it affects treatment ...response remains understudied in pediatric patients. We used single-cell RNA sequencing and single-cell ATAC sequencing to profile 28 patients representing different pAML subtypes at diagnosis, remission and relapse. At diagnosis, cellular composition differed between genetic subgroups. Upon relapse, cellular hierarchies transitioned toward a more primitive state regardless of subtype. Primitive cells in the relapsed tumor were distinct compared to cells at diagnosis, with under-representation of myeloid transcriptional programs and over-representation of other lineage programs. In some patients, this was accompanied by the appearance of a B-lymphoid-like hierarchy. Our data thus reveal the emergence of apparent subtype-specific plasticity upon treatment and inform on potentially targetable processes.
Abstract Purpose A biobank is defined as “a facility for the collection, preservation, storage and supply of biological samples and associated data, which follows standardized operating procedures ...and provides material for scientific and clinical use.” The practice of biobanking must consider the best interests of participants, which is especially complicated in the pediatric setting, where parents or guardians are responsible for consent of their children. Age of participant assent, consent, and reconsent at the age of majority are some of the issues which need to be addressed. Methods We conducted an exploratory survey of four cohorts: (1) adolescents aged 14–18 years treated at British Columbia Children's Hospital, Vancouver, British Columbia, Canada, in the Division of Oncology, Cardiology, or Orthopedics. (2) Parents of the adolescents described in (1). (3) Adolescents aged 14–18 years from high schools in Vancouver, British Columbia, Canada. (4) Parents of the adolescents described in (3). Results We show that clinic participants rated a higher willingness to donate specimens versus school participants. Furthermore, clinic participants felt assent was more important and parental consent alone was insufficient. The median suggested age for assent was 14.5 years among adolescent responses and 16 years from parental responses of both groups. School parents were the most conservative in their responses toward their child's participation in a biobank. Conclusions Adolescents, who were seen in clinics and their parents, had a more altruistic approach toward pediatric biobanking than those surveyed in the school setting. Additionally, parents are less comfortable making decisions regarding biobanking than their adolescent children.
The WHO recommends daily iron supplementation for all women in areas where the population-level anemia prevalence is ≥40%,despite the fact that hemoglobin (Hb) concentration is generally considered ...to be a poor prognostic indicator of iron status.
In this secondary analysis, we investigated the predictive power of ten baseline hematological biomarkers towards a 12-week Hb response to iron supplementation.
Data were obtained from a randomized controlled trial of daily iron supplementation in 407 nonpregnant Cambodian women (18–45 years) who received 60 mg elemental iron as ferrous sulfate for 12 weeks. Ten baseline biomarkers were included: Hb, measured with both a hematology analyzer and a HemoCue; inflammation-adjusted ferritin; soluble transferrin receptor; reticulocyte Hb; hepcidin; mean corpuscular volume; inflammation-adjusted total body iron stores (TBIS); total iron binding capacity; and transferrin saturation. Receiver operating characteristic (ROC) curves from fitted logistic regression models were used to make discrimination comparisons and variable selection methods were used to construct a multibiomarker prognostic model.
Only 25% (n = 95/383) of women who completed the trial experienced a 12-week Hb response ≥10 g/L. The strongest univariate predictors of a Hb response were Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS (AUCROC = 0.81, 0.83, 0.82, and 0.82, respectively), and the optimal cutoffs to identify women who were likely to experience a Hb response were 117 g/L, 17.3 μg/L, 1.98 nmol/L, and 1.95 mg/kg, respectively. Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, and hepcidin had the best combined predictive ability (AUCROC=0.86). Hb measured with the HemoCue had poor discrimination ability (AUCROC = 0.65).
Baseline Hb as measured with a hematology analyzer was as strong a predictor of Hb response to iron supplementation as inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS. This is positive given that the WHO currently uses the population-level anemia prevalence to guide recommendations for untargeted iron supplementation.
KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo ...heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.
Anemia is common in Cambodian women. Potential causes include micronutrient deficiencies, genetic hemoglobin disorders, inflammation, and disease.
We aimed to investigate factors associated with ...anemia (low hemoglobin concentration) in rural Cambodian women (18-45 y) and to investigate the relations between hemoglobin disorders and other iron biomarkers.
Blood samples were obtained from 450 women. A complete blood count was conducted, and serum and plasma were analyzed for ferritin, soluble transferrin receptor (sTfR), folate, vitamin B-12, retinol binding protein (RBP), C-reactive protein (CRP), and α1 acid glycoprotein (AGP). Hemoglobin electrophoresis and multiplex polymerase chain reaction were used to determine the prevalence and type of genetic hemoglobin disorders.
Overall, 54% of women had a genetic hemoglobin disorder, which included 25 different genotypes (most commonly, hemoglobin E variants and α(3.7)-thalassemia). Of the 420 nonpregnant women, 29.5% had anemia (hemoglobin <120 g/L), 2% had depleted iron stores (ferritin <15 μg/L), 19% had tissue iron deficiency (sTfR >8.3 mg/L), <3% had folate deficiency (<3 μg/L), and 1% had vitamin B-12 deficiency (<150 pmol/L). Prevalences of iron deficiency anemia (IDA) were 14.2% and 1.5% in those with and without hemoglobin disorders, respectively. There was no biochemical evidence of vitamin A deficiency (RBP <0.7 μmol/L). Acute and chronic inflammation were prevalent among 8% (CRP >5 mg/L) and 26% (AGP >1 g/L) of nonpregnant women, respectively. By using an adjusted linear regression model, the strongest predictors of hemoglobin concentration were hemoglobin E homozygous disorder and pregnancy status. Other predictors were 2 other heterozygous traits (hemoglobin E and Constant Spring), parity, RBP, log ferritin, and vitamin B-12.
Multiple biomarkers for anemia and iron deficiency were significantly influenced by the presence of hemoglobin disorders, hence reducing their diagnostic sensitivity. Further investigation of the unexpectedly low prevalence of IDA in Cambodian women is warranted.
Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate ...genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A p.Gly82Arg) and YWHAG (aka 14-3-3γ) (c.394C>T p.Arg132Cys), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder’s etiology and genotype-phenotype correlations.
Background
B‐lymphoblastic leukemia (B‐ALL) is the most common childhood malignancy, and its diagnosis requires immunophenotypically demonstrating blast B cell lineage differentiation. Expression of ...myeloperoxidase (MPO) in B‐ALL is well‐described and it has been recognized that a diagnosis of mixed phenotype acute leukemia should be made cautiously if MPO expression is the sole myeloid feature in these cases. We sought to determine whether MPO expression in pediatric B‐ALL was associated with differences in laboratory, immunophenotypic, or clinical features.
Methods
We reviewed clinical, diagnostic bone marrow flow cytometry, and laboratory data for all new B‐ALL diagnoses at our pediatric institution in 5 years. Cases were categorized as MPO positive (MPO+) or negative (MPO−) using a threshold of ≥20% blasts expressing MPO at intensity greater than the upper limit of normal lymphocytes on diagnostic bone marrow flow cytometry.
Results
A total of 148 cases were reviewed, 32 of which (22%) were MPO+. MPO+ B‐ALL was more frequently hyperdiploid and less frequently harbored ETV6‐RUNX1; no MPO+ cases had KMT2A rearrangements or BCR‐ABL1. Although not significantly so, MPO+ B‐ALL was less likely than MPO− B‐ALL to have positive end‐of‐induction minimal residual disease studies (9.4 and 24%, respectively), but relapse rates and stem cell transplantation rates were similar between groups. Aberrant expression of other more typically myeloid markers was similar between these groups.
Conclusion
In our study cohort, MPO+ B‐ALL showed minimal residual disease persistence less often after induction chemotherapy but otherwise had similar clinical outcomes to MPO− B‐ALL, with similar rates of additional myeloid antigen aberrancy.
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