Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma.

Polatuzumab vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B-cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in diffuse large B-cell lymphoma (DLBCL). To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic. Significance: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, they reveal a novel post-translational mechanism used by normal and malignant germinal center B cells to regulate expression of the BCR. See related commentary by Leveille, p. 1577 See related article by Meriranta et al.

Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell-like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-κB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-κB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers. SIGNIFICANCE: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B-dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749.

The Relationship between School Infrastructure and School Nutrition Program Participation and Policies in New York City.

School nutrition programs (SNP) provide much needed access to fruits, vegetables, and other healthy foods at low or no cost. Yet, the infrastructure of school kitchens and cafeteria vary across schools, potentially contributing to systematic barriers for SNP operation and equity. The purpose of this paper is to examine the association between school infrastructure and outcomes including meal participation, untraditional lunch periods, and having an open campus. Regression analyses were conducted using administrative data for 1804 schools and school nutrition manager survey data (n = 821) in New York City (NYC). Co-location was significantly associated with open campus status (OR = 2.84, CI: 1.11, 7.26) and high school breakfast participation (ß = -0.056, p = 0.003). Overcrowding was associated with breakfast (elementary: ß = -0.046, p = 0.03; middle: ß = 0.051, p = 0.04; high: ß = 0.042, p = 0.04) and lunch participation (elementary: ß = -0.031, p = 0.01) and untraditional lunchtimes (elementary: OR = 2.47, CI: 1.05, 5.83). Higher enrollment to cafeteria capacity ratios was associated with breakfast (elementary: ß = -0.025, p = 0.02) and lunch (elementary: ß = -0.015, p = 0.001; high: ß = 0.014, p = 0.02) participation and untraditional lunchtimes (middle: OR = 1.66, CI: 1.03, 2.68). Infrastructure characteristics are an important source of variation across NYC schools that may hinder the equity of school nutrition programs across the city.

Teacher Effects on Student Achievement and Height: A Cautionary Tale.

We apply "value-added" models to estimate the effects of teachers on an outcome they cannot plausibly affect: student height. When fitting commonly estimated models to New York City data, we find that the standard deviation of teacher effects on height is nearly as large as that for math and reading, raising potential concerns about value-added estimates of teacher effectiveness. We consider two explanations: non-random sorting of students to teachers and idiosyncratic classroom-level variation. We cannot rule out sorting on unobservables, but find students are not sorted to teachers based on lagged height. The correlation in teacher effects estimates on height across years and the correlation between teacher effects on height and teacher effects on achievement are insignificant. The large estimated "effects" for height appear to be driven by year-to-year classroom by teacher variation that is not often separable from true effects in models commonly estimated in practice. Reassuringly for use of these models in research settings, models which disentangle persistent effects from transient classroom-level variation yield the theoretically expected effects of zero for teacher value added on height.

Adult Drosophila Lack Hematopoiesis but Rely on a Blood Cell Reservoir at the Respiratory Epithelia to Relay Infection Signals to Surrounding Tissues.

The use of adult Drosophila melanogaster as a model for hematopoiesis or organismal immunity has been debated. Addressing this question, we identify an extensive reservoir of blood cells (hemocytes) at the respiratory epithelia (tracheal air sacs) of the thorax and head. Lineage tracing and functional analyses demonstrate that the majority of adult hemocytes are phagocytic macrophages (plasmatocytes) from the embryonic lineage that parallels vertebrate tissue macrophages. Surprisingly, we find no sign of adult hemocyte expansion. Instead, hemocytes play a role in relaying an innate immune response to the blood cell reservoir: through Imd signaling and the Jak/Stat pathway ligand Upd3, hemocytes act as sentinels of bacterial infection, inducing expression of the antimicrobial peptide Drosocin in respiratory epithelia and colocalizing fat body domains. Drosocin expression in turn promotes animal survival after infection. Our work identifies a multi-signal relay of organismal humoral immunity, establishing adult Drosophila as model for inter-organ immunity.

Efficient derivation of microglia-like cells from human pluripotent stem cells.

Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer's, Parkinson's and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions. These in vitro pluripotent stem cell-derived microglia-like cells (termed pMGLs) faithfully recapitulate the expected ontogeny and characteristics of their in vivo counterparts, and they resemble primary fetal human and mouse microglia. We generated these cells from multiple disease-specific cell lines and find that pMGLs derived from an hES model of Rett syndrome are smaller than their isogenic controls. We further describe a platform to study the integration and live behavior of pMGLs in organotypic 3D cultures. This modular differentiation system allows for the study of microglia in highly defined conditions as they mature in response to developmentally relevant cues, and it provides a framework in which to study the long-term interactions of microglia residing in a tissue-like environment.

The Effect of Breakfast in the Classroom on Obesity and Academic Performance: Evidence from New York City.

Participation in the federally subsidized school breakfast program often falls well below its lunchtime counterpart. To increase take-up, many districts have implemented Breakfast in the Classroom (BIC), offering breakfast directly to students at the start of the school day. Beyond increasing participation, advocates claim BIC improves academic performance, attendance, and engagement. Others caution BIC has deleterious effects on child weight. We use the implementation of BIC in New York City (NYC) to estimate its impact on meals program participation, body mass index (BMI), achievement, and attendance. While we find large effects on participation, our findings provide no evidence of hoped-for gains in academic performance, or of feared increases in obesity. The policy case for BIC will depend upon reductions in hunger and food insecurity for disadvantaged children, or its longer-term effects.

Neighborhoods, Schools and Obesity: The Potential for Place-Based Approaches to Reduce Childhood Obesity.

A common policy approach to reducing childhood obesity aims to shape the environment in which children spend most of their time: neighborhoods and schools. This paper uses richly detailed data on the body mass index (BMI) of all New York City public school students in grades K-8 to assess the potential for place-based approaches to reduce child obesity. We document variation in the prevalence of obesity across NYC public schools and census tracts, and then estimate the extent to which this variation can be explained by differences in individual-level predictors (such as race and household income). Both unadjusted and adjusted variability across neighborhoods and schools suggest place-based policies have the potential to meaningfully reduce child obesity, but under most realistic scenarios the improvement would be modest.

Not just for poor kids: The impact of universal free school breakfast on meal participation and student outcomes.

This paper examines the impact of the implementation of a universal free school breakfast policy on meals program participation, attendance, and academic achievement. In 2003, New York City made school breakfast free for all students regardless of income, while increasing the price of lunch for those ineligible for meal subsidies. Using a difference-indifference estimation strategy, we derive plausibly causal estimates of the policy's impact by exploiting within and between group variation in school meal pricing before and after the policy change. Our estimates suggest that the policy resulted in small increases in breakfast participation both for students who experienced a decrease in the price of breakfast and for free-lunch eligible students who experienced no price change. The latter suggests that universal provision may alter behavior through mechanisms other than price, highlighting the potential merits of universal provision over targeted services. We find limited evidence of policy impacts on academic outcomes.

The relative geographic immobility of new registered nurses calls for new strategies to augment that workforce.

Little is known about registered nurses' geographic mobility after they earn their first professional degree and become licensed to practice. Through a cross-sectional mailed survey of newly licensed registered nurses in fifteen states, we found that 52.5 percent work within forty miles of where they attended high school. Our complementary analysis of Census Bureau data shows that next to teaching, nursing is one of the least mobile professions for women, for reasons that remain unclear. To ensure that underserved areas have an adequate workforce of registered nurses, policy makers should expand the number of educational programs in these areas; fund programs that provide incentives to young people from these areas to attend nursing programs; consider supporting extension programs from accredited nursing schools; and review admission policies for nursing programs and the financial aid they offer. If states find it difficult to retain out-of-state graduates, giving preference to in-state applicants may make sense. Finally, programs and policies that offer financial incentives to attract registered nurses to underserved areas, such as the National Health Service Corps and the Area Health Education Centers, are critically important. When sufficiently funded, such programs could serve to offset the low mobility of new registered nurses that we observed.

Commuting to work: RN travel time to employment in rural and urban areas.

PURPOSE: To investigate the variation in average daily travel time to work among registered nurses (RNs) living in urban, suburban, and rural areas. We examine how travel time varies across RN characteristics, job setting, and availability of local employment opportunities. METHOD: Descriptive statistics and linear regression using a 5% sample from the 2000 Census and a longitudinal survey of newly licensed RNs (NLRN). Travel time for NLRN respondents was estimated using geographic information systems (GIS) software. FINDINGS: In the NLRN, rural nurses and those living in small towns had significantly longer average commute times. Young married RNs and RNs with children also tended to have longer commute times, as did RNs employed by hospitals. CONCLUSIONS: The findings indicate that travel time to work varies significantly across locale types. Further research is needed to understand whether and to what extent lengthy commute times impact RN workforce needs in rural and urban areas.