Most Short Children with Cystic Fibrosis Do Not Catch Up by Adulthood.

Poor linear growth is common in children with cystic fibrosis (CF) and predicts pulmonary status and mortality. Growth impairment develops in infancy, prior to pulmonary decline and despite aggressive nutritional measures. We hypothesized that growth restriction during early childhood in CF is associated with reduced adult height. We used the Cystic Fibrosis Foundation (CFF) patient registry to identify CF adults between 2011 and 2015 (ages 18-19 y, n = 3655) and had height for age (HFA) records between ages 2 and 4 y. We found that only 26% CF adults were ≥median HFA and 25% were <10th percentile. Between 2 and 4 years, those with height < 10th percentile had increased odds of being <10th percentile in adulthood compared to children ≥ 10th percentile (OR = 7.7). Of HFA measured between the 10th and 25th percentiles at ages 2-4, 58% were <25th percentile as adults. Only 13% between the 10th and 25th percentile HFA at age 2-4 years were >50th percentile as adults. Maximum height between ages 2 and 4 highly correlated with adult height. These results demonstrate that low early childhood CF height correlates with height in adulthood. Since linear growth correlates with lung growth, identifying both risk factors and interventions for growth failure (nutritional support, confounders of clinical care, and potential endocrine involvement) could lead to improved overall health.

Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma.

In glioma, microglia and macrophages are the largest population of tumor-infiltrating cells, referred to as glioma associated macrophages (GAMs). Herein, we sought to determine the role of Suppressor of Cytokine Signaling 3 (SOCS3), a negative regulator of Signal Transducer and Activator of Transcription 3 (STAT3), in GAM functionality in glioma. We utilized a conditional model in which SOCS3 deletion is restricted to the myeloid cell population. We found that SOCS3-deficient bone marrow-derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines when exposed to glioma tumor cell conditioned medium in vitro. Moreover, we found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors in vivo. Although intracranial tumors from mice with SOCS3-deficient myeloid cells appear histologically similar to control mice, we observed that loss of SOCS3 in myeloid cells results in decreased M2 polarized macrophage infiltration in the tumors. Furthermore, loss of SOCS3 in myeloid cells results in increased CD8+ T-cell and decreased regulatory T-cell infiltration in the tumors. These findings demonstrate a beneficial effect of M1 polarized macrophages on suppressing glioma tumor growth, and highlight the importance of immune cells in the tumor microenvironment.

Loss of tumor suppressive microRNA-31 enhances TRADD/NF-κB signaling in glioblastoma.

Glioblastomas (GBMs) are deadly tumors of the central nervous system. Most GBM exhibit homozygous deletions of the CDKN2A and CDKN2B tumor suppressors at 9p21.3, although loss of CDKN2A/B alone is insufficient to drive gliomagenesis. MIR31HG, which encodes microRNA-31 (miR-31), is a novel non-coding tumor suppressor positioned adjacent to CDKN2A/B at 9p21.3. We have determined that miR-31 expression is compromised in >72% of all GBM, and for patients, this predicts significantly shortened survival times independent of CDKN2A/B status. We show that miR-31 inhibits NF-κB signaling by targeting TRADD, its upstream activator. Moreover, upon reintroduction, miR-31 significantly reduces tumor burden and lengthens survival times in animal models. As such, our work identifies loss of miR-31 as a novel non-coding tumor-driving event in GBM.