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The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To investigate a framework of correlates of both mental illness and wellbeing in a large, current, and nationally representative sample of children in the United Kingdom., Method: An ecologic framework of correlates including individual (sociodemographic and human capital), family, social, and wider environmental factors were examined in 12,347 children aged 11 years old from the UK Millennium Cohort Study. Mental illness and wellbeing scores were standardized to allow comparisons, and the variance explained by the different predictors was estimated., Results: Mental illness and wellbeing were weakly correlated in children (r = 0.2), and their correlates were similar in some instances (e.g., family structure, sibling bullying, peer problems) but differed in others (e.g., family income, perceived socioeconomic status, cognitive ability, health status, neighborhood safety). The predictors included in the study explained 47% of the variance in symptoms of mental illness, with social relationships, home environment, parent health, cognitive ability, socioeconomic status, and health factors predicting large amounts of variance. A comparatively lower 26% of the variance in wellbeing was explained by the study variables, with wider environment, social relationships, perceived socioeconomic status, and home environment predicting the most variance., Conclusion: Correlates of children's mental illness and wellbeing are largely distinct, stressing the importance of considering these concepts separately and avoiding their conflation. This study highlights the relevance of these findings for understanding social gradients in mental health through the life course and the conceptualization and development of mental illness and wellbeing in childhood as precursors to lifelong development in these domains., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.

The characterization of many cytokines involved in the control of hematopoiesis has led to intense investigation into their potential use in ex vivo culture to expand progenitor numbers. We have established the optimum ex vivo culture conditions that allow substantial amplification of transient engrafting murine stem cells and which, simultaneously, augment the ability to sustain serial bone marrow transplantation (BMT). Short-term incubation of unfractionated BM cells in liquid culture with stem cell factor (SCF) and interleukin-11 (IL-11) produced a 50-fold amplification of clonogenic multipotential progenitors (CFU-A). Following such ex vivo expansion, substantially fewer cells were required to rescue lethally irradiated mice. When transplanted in cell doses above threshold for engraftment, BM cells expanded ex vivo resulted in significantly more rapid hematopoietic recovery. In a serial transplantation model, unmanipulated BM was only able to consistently sustain secondary BMT recipients, but BM expanded ex vivo has sustained quaternary BMT recipients that remain alive and well more than 140 days after 4th degree BMT. These results show augmentation of both short-term recovery posttransplant and the ability to serially transplant marrow by preincubation in culture with SCF and IL-11.

Viral-associated haemophagocyte syndrome in response to infection with human parvovirus B19 was seen in 2 patients with hereditary spherocytosis. Depressed reticulocyte response during acute parvovirus infection is a known cause of hypoproliferative crises in patients with reduced erythrocyte lifespan; the observation of parvovirus-associated haemophagocytosis could account for the pancytopenia that may accompany human parvovirus B19 infection.

Weekly serum zinc levels during the neonatal period have been obtained in 17 preterm infants randomly assigned to a prospective feeding study. Nine neonates received a standard regimen of naso-jejunal feedings (group I) and eight matched infants received total parenteral nutrition (group II) for the first 2 wk, followed by enteral intake for the last 2 wk of the study period. No patient received supplemental zinc intake. Base-line serum zinc levels obtained before beginning feedings at 2 days of age were in the normal range and not significantly different, 121 +/- 15 and 135 +/- 8 micrograms/dl in groups I and II, respectively (mean +/- SEM). Serial serum zinc levels decreased progressively in both groups during the 4-wk study period, reaching a low of 80 +/- 7 micrograms/dl in group I and 85 +/- 10 micrograms/dl in group II. The progressive decline in serum zinc levels is postulated to be indicative of tissue depletion of zinc. Our data suggest that preterm infants fed either by short-term total parenteral nutrition or by transpyloric enteral feedings are at risk for marginal zinc deficiency states.