Restoration of RARbeta1' expression may overcome retinoid resistance in lung carcinogenesis.

Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.

Mesenchymal stem cells (MSCs) represent a potentially revolutionary therapy for a wide variety of pediatric diseases, but the optimal cell‐based therapeutics for such diversity have not yet been specified. The published clinical trials for pediatric pulmonary, cardiac, orthopedic, endocrine, neurologic, and hematologic diseases provide evidence that MSCs are indeed efficacious, but the significant heterogeneity in therapeutic approaches between studies raises new questions. The purpose of this review is to stimulate new preclinical and clinical trials to investigate these factors. First, we discuss recent clinical trials for pediatric diseases studying MSCs obtained from bone marrow, umbilical cord and umbilical cord blood, placenta, amniotic fluid, and adipose tissue. We then identify factors, some unique to pediatrics, which must be examined to optimize therapeutic efficacy, including route of administration, dose, timing of administration, the role of ex vivo differentiation, cell culture techniques, donor factors, host factors, and the immunologic implications of allogeneic therapy. Finally, we discuss some of the practicalities of bringing cell‐based therapy into the clinic, including regulatory and manufacturing considerations. The aim of this review is to inform future studies seeking to maximize therapeutic efficacy for each disease and for each patient. Stem Cells Translational Medicine 2017;6:539–565

Systemic sepsis is a known risk factor for bronchopulmonary dysplasia (BPD) in premature infants, a disease characterized by dysregulated angiogenesis and impaired vascular and alveolar development. We have previoulsy reported that systemic endotoxin dysregulates pulmonary angiogenesis resulting in alveolar simplification mimicking BPD in neonatal mice, but the underlying mechanisms remain unclear. We undertook an unbiased discovery approach to identify novel signaling pathways programming sepsis-induced deviant lung angiogenesis. Pulmonary endothelial cells (EC) were isolated for RNA-Seq from newborn C57BL/6 mice treated with intraperitoneal lipopolysaccharide (LPS) to mimic systemic sepsis. LPS significantly differentially-regulated 269 genes after 6 h, and 1,934 genes after 24 h. Using bioinformatics, we linked 6 h genes previously unknown to be modulated by LPS to 24 h genes known to regulate angiogenesis/vasculogenesis to identify pathways programming deviant angiogenesis. An immortalized primary human lung EC (HPMEC-im) line was generated by SV40 transduction to facilitate mechanistic studies. RT-PCR and transcription factor binding analysis identified FOSL1 (FOS like 1) as a transcriptional regulator of LPS-induced downstream angiogenic or vasculogenic genes. Over-expression and silencing studies of FOSL1 in immortalized and primary HPMEC demonstrated that baseline and LPS-induced expression of ADAM8, CXCR2, HPX, LRG1, PROK2, and RNF213 was regulated by FOSL1. FOSL1 silencing impaired LPS-induced in vitro HPMEC angiogenesis. In conclusion, we identified FOSL1 as a novel regulator of sepsis-induced deviant angiogenic signaling in mouse lung EC and human fetal HPMEC. Bronchopulmonary dysplasia (BPD) is a developmental lung disorder characterized by simplified alveoli and dysmorphic pulmonary vasculature 1-6. BPD affects approximately 40% of infants born at ≤ 28 weeks gestational age with up to 29% mortality 7. Recent studies have found that maternal chorioamnionitis increases the incidence of BPD and perinatal mortality 8 , and postnatal sepsis or pneumonia increases the risk of preterm infants developing BPD 9. While oxygen toxicity, mechanical ventilation, and inflammation are traditional risk factors for the development of BPD, systemic sepsis has emerged as a significant risk factor for BPD 10-13. Systemic sepsis caused by Gram-positive and Gram-negative bacteria is common in premature infants, and is associated with BPD 9,14-16. in addition to airway colonization with Gram negative bacilli correlates with severe BPD 17. However, the mechanisms underlying sepsis-induced neonatal acute lung injury and alveolar remodeling seen in BPD remain understudied 3,18-21. We have previously shown that postnatal systemic lipopolysaccharide (LPS) disrupts lung development in newborn mice, leading to alveolar simplification in a Nox2-dependent manner 1. However, relatively little is known about the impact of LPS on the developing lung vasculature. In human BPD and hyperoxia models of experimental BPD, several researche...

Infection with nontuberculous mycobacteria (NTM) is a complication of lung disease in immunocompromised patients, including those with human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). The most widespread, disease-causing NTM is Mycobacterium avium complex (MAC), which colonizes the lungs as a combination of Mycobacterium avium, Mycobacterium intracellulare, and other mycobacterial species. While combination drug therapy exists for MAC colonization, there is no cure. Therapeutic development to treat MAC has been difficult because of the slow-growing nature of the bacterial complex, limiting the ability to characterize the bacteria’s growth in response to new therapeutics. The development of a technology that allows observation of both the MAC predominant strains and MAC could provide a means to develop new therapeutics to treat NTM. We have developed a new methodology in which M. avium and M. intracellulare can be optimally grown in short term culture to study each strain independently and in combination, as a monitor of growth kinetics and efficient therapeutic testing protocols.

ObjectiveA portable, low-field MRI system is now Food and Drug Administration cleared and has been shown to be safe and useful in adult intensive care unit settings. No neonatal studies have been performed. The objective is to assess our preliminary experience and assess feasibility of using the portable MRI system at the bedside in a neonatal intensive care unit (NICU) at a quaternary children’s hospital.Study designThis was a single-site prospective cohort study in neonates ≥2 kg conducted between October and December 2020. All parents provided informed consent. Neonates underwent portable MRI examination in the NICU with support equipment powered on and attached to the neonate during the examination. A paediatric radiologist interpreted each portable MRI examination. The study outcome variable was percentage of portable MRI examinations completed without artefacts that would hinder diagnosis. Findings were compared between portable MRI examinations and standard of care examinations.ResultsEighteen portable, low-field MRI examinations were performed on 14 neonates with an average age of 29.7 days (range 1–122 days). 94% (17 of 18) of portable MRI examinations were acquired without significant artefact. Significant intracranial pathology was visible on portable MRI, but subtle abnormalities were missed. The examination reads were concordant in 59% (10 of 17) of cases and significant pathology was missed in 12% (2 of 17) of cases.ConclusionThis single-centre series demonstrated portable MRI examinations can be performed safely with standard patient support equipment present in the NICU. These findings demonstrate that portable MRI could be used in the future to guide care in the NICU setting.Trial registration numberNCT04629469.

ImportanceAnti–vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified.ObjectiveTo determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment.Design, Setting, and ParticipantsThis multicenter retrospective cohort study took place at neonatal intensive care units of 48 children’s hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation.ExposuresAnti-VEGF therapy vs laser photocoagulation.Main Outcomes and MeasuresNew receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening.ResultsAmong 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks’ postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10).Conclusions and RelevanceAnti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

The intestine is extremely dynamic and the epithelial cells that line the intestine get replaced every 3–5 days by highly proliferative intestinal stem cells (ISCs). The instructions for ISCs to self-renew or to differentiate come as cues from their surrounding microenvironment or their niche. A small number of evolutionarily conserved signaling pathways act as a critical regulator of the stem cells in the adult intestine, and these pathways are well characterized. However, the mechanisms, nutritional, and environmental signals that help establish the stem cell niche in the neonatal intestine are less studied. Deciphering the key signaling pathways that regulate the development and maintenance of the stem cells is particularly important to understanding how the intestine regenerates from necrotizing enterocolitis, a devastating disease in newborn infants characterized by inflammation, tissues necrosis, and stem cell injury. In this review, we piece together current knowledge on morphogenetic and immune pathways that regulate intestinal stem cell in neonates and highlight how the cross talk among these pathways affect tissue regeneration. We further discuss how these key pathways are perturbed in NEC and review the scientific knowledge relating to options for stem cell therapy in NEC gleaned from pre-clinical experimental models of NEC.