147 results on '"Misty Good"'
Search Results
2. The role of human milk nutrients in preventing necrotizing enterocolitis
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Ahmad S. Sami, Lauren C. Frazer, Claire M. Miller, Dhirendra K. Singh, Lynda G. Clodfelter, Kelly A. Orgel, and Misty Good
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breast milk ,neonates ,prematurity ,necrotizing enterocolitis (NEC) ,intestine ,nutrients ,Pediatrics ,RJ1-570 - Abstract
Necrotizing enterocolitis (NEC) is an intestinal disease that primarily impacts preterm infants. The pathophysiology of NEC involves a complex interplay of factors that result in a deleterious immune response, injury to the intestinal mucosa, and in its most severe form, irreversible intestinal necrosis. Treatments for NEC remain limited, but one of the most effective preventative strategies for NEC is the provision of breast milk feeds. In this review, we discuss mechanisms by which bioactive nutrients in breast milk impact neonatal intestinal physiology and the development of NEC. We also review experimental models of NEC that have been used to study the role of breast milk components in disease pathophysiology. These models are necessary to accelerate mechanistic research and improve outcomes for neonates with NEC.
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- 2023
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3. Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics
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Stephen Mackay, Lauren C. Frazer, Grace K. Bailey, Claire M. Miller, Qingqing Gong, Olivia N. Dewitt, Dhirendra K. Singh, and Misty Good
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necrotizing enterocolitis ,prematurity ,aptamer ,SomaScan ,serum ,biomarker ,Pediatrics ,RJ1-570 - Abstract
IntroductionNecrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice.MethodsIn this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups.ResultsWe detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC.DiscussionThese findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.
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- 2023
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4. Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis–on-a-chip
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Wyatt E. Lanik, Cliff J. Luke, Lila S. Nolan, Qingqing Gong, Lauren C. Frazer, Jamie M. Rimer, Sarah E. Gale, Raymond Luc, Shay S. Bidani, Carrie A. Sibbald, Angela N. Lewis, Belgacem Mihi, Pranjal Agrawal, Martin Goree, Marlie Maestas, Elise Hu, David G. Peters, and Misty Good
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Cell biology ,Inflammation ,Medicine - Abstract
Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants that is associated with an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. We describe an in vitro model of the human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology. This model utilizes intestinal enteroids grown from surgically harvested intestinal tissue from premature infants and cocultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology by adding infant-derived microbiota. This model, named NEC-on-a-Chip, simulates the predominant features of NEC, including significant upregulation of proinflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation, and disrupted epithelial barrier integrity. NEC-on-a-Chip provides an improved preclinical model of NEC that facilitates comprehensive analysis of the pathophysiology of NEC using precious clinical samples. This model is an advance toward a personalized medicine approach to test new therapeutics for this devastating disease.
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- 2023
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5. Fecal Keratin 8 Is a Noninvasive and Specific Marker for Intestinal Injury in Necrotizing Enterocolitis
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Kewei Wang, Guozhong Tao, Zhen Sun, Jingjing Wei, Junlin Liu, Jordan Taylor, Michelle Gibson, Mirko Mostaghimi, Misty Good, and Karl G. Sylvester
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Specific biomarkers of intestinal injury associated with necrotizing enterocolitis (NEC) are needed to diagnose and monitor intestinal mucosal injury and recovery. This study aims to develop and test a modified enzyme-linked immunosorbent assay (ELISA) protocol to detect the total keratin 8 (K8) in the stool of newborns with NEC and investigate the clinical value of fecal K8 as a marker of intestinal injury specifically associated with NEC. We collected fecal samples from five newborns with NEC and five gestational age-matched premature neonates without NEC at the Lucile Packard Children’s Hospital Stanford and Washington University School of Medicine, respectively. Fecal K8 levels were measured using a modified ELISA protocol and Western blot, and fecal calprotectin was measured using a commercial ELISA kit. Clinical data, including gestational age, birth weight, Bell stage for NEC, feeding strategies, total white blood cell (WBC) count, and other pertinent clinical variables, were collected and analyzed. Fecal K8 levels were significantly higher in the pre-NEC group (1–2 days before diagnosis of NEC) and NEC group than those in the non-NEC group (p=0.013, p=0.041). Moreover, fecal K8 was relatively higher at the onset of NEC and declined after the resolution of the disease (p=0.019). Results with similar trends to fecal K8 were also seen in fecal calprotectin (p=0.046), but not seen in total WBC count (p=0.182). In conclusion, a modified ELISA protocol for the total K8 protein was successfully developed for the detection of fecal K8 in the clinical setting of premature newborns with NEC. Fecal K8 is noted to be significantly increased in premature newborns with NEC and may, therefore, serve as a noninvasive and specific marker for intestinal epithelial injury associated with NEC.
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- 2023
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6. Necrotizing enterocolitis: Bench to bedside approaches and advancing our understanding of disease pathogenesis
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Dhirendra K. Singh, Claire M. Miller, Kelly A. Orgel, Mili Dave, Stephen Mackay, and Misty Good
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intestinal development ,neonates ,prematurity ,necrotizing enterocolitis ,intestinal epithelium ,Pediatrics ,RJ1-570 - Abstract
Necrotizing enterocolitis (NEC) is a devastating, multifactorial disease mainly affecting the intestine of premature infants. Recent discoveries have significantly enhanced our understanding of risk factors, as well as, cellular and genetic mechanisms of this complex disease. Despite these advancements, no essential, single risk factor, nor the mechanism by which each risk factor affects NEC has been elucidated. Nonetheless, recent research indicates that maternal factors, antibiotic exposure, feeding, hypoxia, and altered gut microbiota pose a threat to the underdeveloped immunity of preterm infants. Here we review predisposing factors, status of unwarranted immune responses, and microbial pathogenesis in NEC based on currently available scientific evidence. We additionally discuss novel techniques and models used to study NEC and how this research translates from the bench to the bedside into potential treatment strategies.
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- 2023
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7. Lysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins
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Cliff J. Luke, Stephanie Markovina, Misty Good, Ira E. Wight, Brian J. Thomas, John M. Linneman, Wyatt E. Lanik, Olga Koroleva, Maggie R. Coffman, Mark T. Miedel, Qingqing Gong, Arlise Andress, Marlene Campos Guerrero, Songyan Wang, LiYun Chen, Wandy L. Beatty, Kelsey N. Hausmann, Frances V. White, James A. J. Fitzpatrick, Anthony Orvedahl, Stephen C. Pak, and Gary A. Silverman
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Biology (General) ,QH301-705.5 - Abstract
Cliff Luke et al. report that lysoptosis is a eukaryotic stand-alone regulated cell death pathway. They identify that this new cell death modality predominates in the absence of neutralizing endogenous inhibitors.
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- 2022
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8. A protocol for the induction of experimental necrotizing enterocolitis in neonatal mice
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Lila S. Nolan, Qingqing Gong, Heather N. Hofmeister, and Misty Good
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Developmental biology ,Health Sciences ,Microbiology ,Model Organisms ,Molecular Biology ,Science (General) ,Q1-390 - Abstract
Summary: Recapitulating human NEC using animal models has been insightful in dissecting the signaling pathways, immune-mediated mechanisms, genetic signatures, and the intestinal architecture of NEC. This protocol describes an in vivo murine NEC model, using hypoxia and formula containing lipopolysaccharide and enteric bacteria derived from an infant with NEC. With this mouse model, we aim to further dissect NEC pathogenesis and develop new therapeutic strategies.For complete details on the use and execution of this protocol, please refer to Mihi et al. (2021).
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- 2021
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9. A Promising Genetic Target for a Deadly Disease: Single Immunoglobulin Interleukin 1 (SIGIRR) Mutations in Necrotizing Enterocolitis
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Misty Good, MD, MS and Camilia R. Martin, MD, MS
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Published
- 2022
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10. Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration
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Belgacem Mihi, Qingqing Gong, Lila S. Nolan, Sarah E. Gale, Martin Goree, Elise Hu, Wyatt E. Lanik, Jamie M. Rimer, Victoria Liu, Olivia B. Parks, Angela N. Lewis, Pranjal Agrawal, Marie L. Laury, Pawan Kumar, Elizabeth Huang, Shay S. Bidani, Cliff J. Luke, Jay K. Kolls, and Misty Good
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interleukin-22 ,necrotizing enterocolitis ,epithelial cells ,microbiome ,regeneration ,intestinal immunity ,Medicine (General) ,R5-920 - Abstract
Summary: Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC.
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- 2021
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11. Gestational Age-Specific Complete Blood Count Signatures in Necrotizing Enterocolitis
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Julia M. Pantalone, Silvia Liu, Oluwabunmi O. Olaloye, Erica C. Prochaska, Toby Yanowitz, Melissa M. Riley, Justin R. Buland, Beverly S. Brozanski, Misty Good, and Liza Konnikova
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immunology ,complete blood count ,gestational age ,necrotizing entercolitis ,pre-maturity ,Pediatrics ,RJ1-570 - Abstract
Objective: Necrotizing enterocolitis (NEC) is characterized by peripheral cell abnormalities, yet few studies have analyzed the complete blood count (CBC) specifically by gestational age (GA). Our objective was to describe GA-specific immune abnormalities in NEC through a comprehensive analysis of the CBC differential.Methods: Using a cohort of 246 infants (177 cases, 69 controls) admitted to neonatal intensive care units at a single institution, we retrospectively analyzed CBCs around illness onset in NEC cases compared with controls. Cases included surgical NEC (S-NEC, 34.5%) and medical NEC (M-NEC, 65.5%). Infants were divided into those born at GA
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- 2021
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12. Interleukin-22 Inhibits Respiratory Syncytial Virus Production by Blocking Virus-Mediated Subversion of Cellular Autophagy
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Sudipta Das, Claudette St. Croix, Misty Good, Jie Chen, Jinming Zhao, Sanmei Hu, Mark Ross, Michael M. Myerburg, Joseph M. Pilewski, John Williams, Sally E. Wenzel, Jay K. Kolls, Anuradha Ray, and Prabir Ray
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Immunology ,Virology ,Cell Biology ,Science - Abstract
Summary: Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular autophagic machinery, and knockdown of LC3B ablated virus production. RSV subverted LC3B with evidence of co-localization and caused a significant reduction in autophagic flux, both reversed by IL-22 treatment. Our findings inform a previously unrecognized anti-viral effect of IL-22 that can be harnessed to prevent RSV-induced severe respiratory disease.
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- 2020
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13. Untargeted Metabolomic Analysis of Human Milk from Mothers of Preterm Infants
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Lila S. Nolan, Angela N. Lewis, Qingqing Gong, James J. Sollome, Olivia N. DeWitt, Robert D. Williams, and Misty Good
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breast milk ,necrotizing enterocolitis ,metabolomics ,metabolites ,human milk ,prematurity ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The application of metabolomics in neonatology offers an approach to investigate the complex relationship between nutrition and infant health. Characterization of the metabolome of human milk enables an investigation into nutrients that affect the neonatal metabolism and identification of dietary interventions for infants at risk of diseases such as necrotizing enterocolitis (NEC). In this study, we aimed to identify differences in the metabolome of breast milk of 48 mothers with preterm infants with NEC and non-NEC healthy controls. A minimum significant difference was observed in the human milk metabolome between the mothers of infants with NEC and mothers of healthy control infants. However, significant differences in the metabolome related to fatty acid metabolism, oligosaccharides, amino sugars, amino acids, vitamins and oxidative stress-related metabolites were observed when comparing milk from mothers with control infants of ≤1.0 kg birth weight and >1.5 kg birth weight. Understanding the functional biological features of mothers’ milk that may modulate infant health is important in the future of tailored nutrition and care of the preterm newborn.
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- 2021
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14. Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice
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Hala Chaaban, Kathryn Burge, Jeffrey Eckert, MaJoi Trammell, David Dyer, Ravi S. Keshari, Robert Silasi, Girija Regmi, Cristina Lupu, Misty Good, Steven J. McElroy, and Florea Lupu
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necrotizing enterocolitis ,intestinal barrier ,human milk bioactive factors ,hyaluronan ,preterm infants ,prebiotics ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota; the implications of these responses need to be determined.
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- 2021
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15. The Role of Human Milk Oligosaccharides and Probiotics on the Neonatal Microbiome and Risk of Necrotizing Enterocolitis: A Narrative Review
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Lila S. Nolan, Jamie M. Rimer, and Misty Good
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prematurity ,newborn ,necrotizing enterocolitis ,microbiome ,human milk oligosaccharide ,probiotic ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Preterm infants are a vulnerable population at risk of intestinal dysbiosis. The newborn microbiome is dominated by Bifidobacterium species, though abnormal microbial colonization can occur by exogenous factors such as mode of delivery, formula feeding, and exposure to antibiotics. Therefore, preterm infants are predisposed to sepsis and necrotizing enterocolitis (NEC), a fatal gastrointestinal disorder, due to an impaired intestinal barrier, immature immunity, and a dysbiotic gut microbiome. Properties of human milk serve as protection in the prevention of NEC. Human milk oligosaccharides (HMOs) and the microbiome of breast milk are immunomodulatory components that provide intestinal homeostasis through regulation of the microbiome and protection of the intestinal barrier. Enteral probiotic supplements have been trialed to evaluate their impact on establishing intestinal homeostasis. Here, we review the protective role of HMOs, probiotics, and synbiotic combinations in protecting a vulnerable population from the pathogenic features associated with necrotizing enterocolitis.
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- 2020
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16. Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis.
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Shiloh R Lueschow, Jessica Stumphy, Huiyu Gong, Stacy L Kern, Timothy G Elgin, Mark A Underwood, Karen M Kalanetra, David A Mills, Melissa H Wong, David K Meyerholz, Misty Good, and Steven J McElroy
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Medicine ,Science - Abstract
Necrotizing enterocolitis (NEC) remains the leading cause of gastrointestinal morbidity and mortality in premature infants. Human and animal studies suggest a role for Paneth cells in NEC pathogenesis. Paneth cells play critical roles in host-microbial interactions and epithelial homeostasis. The ramifications of eliminating Paneth cell function on the immature host-microbial axis remains incomplete. Paneth cell function was depleted in the immature murine intestine using chemical and genetic models, which resulted in intestinal injury consistent with NEC. Paneth cell depletion was confirmed using histology, electron microscopy, flow cytometry, and real time RT-PCR. Cecal samples were analyzed at various time points to determine the effects of Paneth cell depletion with and without Klebsiella gavage on the microbiome. Deficient Paneth cell function induced significant compositional changes in the cecal microbiome with a significant increase in Enterobacteriacae species. Further, the bloom of Enterobacteriaceae species that occurs is phenotypically similar to what is seen in human NEC. This further strengthens our understanding of the importance of Paneth cells to intestinal homeostasis in the immature intestine.
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- 2018
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17. Regulation of Dendritic Cell Function by Vitamin D
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Myriam Barragan, Misty Good, and Jay K. Kolls
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vitamin D ,vitamin D receptor ,dendritic cells ,innate and adaptive immunity ,interleukins ,cytokines ,inflammation ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)2D3, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)2D3-Vitamin D3 complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health.
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- 2015
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18. Editorial: Organogenesis: From Development to Disease
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Sunder Sims-Lucas, Misty Good, and Seppo J. Vainio
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animal ,inflammation ,kidney development ,bowel disease ,diabetes mellitus ,type 1 ,Biology (General) ,QH301-705.5 - Published
- 2017
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19. Stem Cell-Derived Models of Viral Infections in the Gastrointestinal Tract
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Wyatt E. Lanik, Madison A. Mara, Belgacem Mihi, Carolyn B. Coyne, and Misty Good
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enteroids ,organoids ,intestinal stem cells ,mini-guts ,enteroviruses ,Microbiology ,QR1-502 - Abstract
Studies on the intestinal epithelial response to viral infection have previously been limited by the absence of in vitro human intestinal models that recapitulate the multicellular complexity of the gastrointestinal tract. Recent technological advances have led to the development of “mini-intestine” models, which mimic the diverse cellular nature and physiological activity of the small intestine. Utilizing adult or embryonic intestinal tissue, enteroid and organoid systems, respectively, represent an opportunity to effectively model cellular differentiation, proliferation, and interactions that are specific to the specialized environment of the intestine. Enteroid and organoid systems represent a significant advantage over traditional in vitro methods because they model the structure and function of the small intestine while also maintaining the genetic identity of the host. These more physiologic models also allow for novel approaches to investigate the interaction of enteric viruses with the gastrointestinal tract, making them ideal to study the complexities of host-pathogen interactions in this unique cellular environment. This review aims to provide a summary on the use of human enteroid and organoid systems as models to study virus pathogenesis.
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- 2018
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20. Gut bacteria are rarely shared by co-hospitalized premature infants, regardless of necrotizing enterocolitis development
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Tali Raveh-Sadka, Brian C Thomas, Andrea Singh, Brian Firek, Brandon Brooks, Cindy J Castelle, Itai Sharon, Robyn Baker, Misty Good, Michael J Morowitz, and Jillian F Banfield
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Microbiota ,necrotizing enterocolitis ,gut microbial colonization ,nosocomial infection ,preterm infant ,metagenomics ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Premature infants are highly vulnerable to aberrant gastrointestinal tract colonization, a process that may lead to diseases like necrotizing enterocolitis. Thus, spread of potential pathogens among hospitalized infants is of great concern. Here, we reconstructed hundreds of high-quality genomes of microorganisms that colonized co-hospitalized premature infants, assessed their metabolic potential, and tracked them over time to evaluate bacterial strain dispersal among infants. We compared microbial communities in infants who did and did not develop necrotizing enterocolitis. Surprisingly, while potentially pathogenic bacteria of the same species colonized many infants, our genome-resolved analysis revealed that strains colonizing each baby were typically distinct. In particular, no strain was common to all infants who developed necrotizing enterocolitis. The paucity of shared gut colonizers suggests the existence of significant barriers to the spread of bacteria among infants. Importantly, we demonstrate that strain-resolved comprehensive community analysis can be accomplished on potentially medically relevant time scales.
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- 2015
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21. Mucosa-associated bacterial diversity in necrotizing enterocolitis.
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Rachel Brower-Sinning, Diana Zhong, Misty Good, Brian Firek, Robyn Baker, Chhinder P Sodhi, David J Hackam, and Michael J Morowitz
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Medicine ,Science - Abstract
Previous studies of infant fecal samples have failed to clarify the role of gut bacteria in the pathogenesis of NEC. We sought to characterize bacterial communities within intestinal tissue resected from infants with and without NEC.26 intestinal samples were resected from 19 infants, including 16 NEC samples and 10 non-NEC samples. Bacterial 16S rRNA gene sequences were amplified and sequenced. Analysis allowed for taxonomic identification, and quantitative PCR was used to quantify the bacterial load within samples.NEC samples generally contained an increased total burden of bacteria. NEC and non-NEC sample sets were both marked by high inter-individual variability and an abundance of opportunistic pathogens. There was no statistically significant distinction between the composition of NEC and non-NEC microbial communities. K-means clustering enabled us to identify several stable clusters, including clusters of NEC and midgut volvulus samples enriched with Clostridium and Bacteroides. Another cluster containing both NEC and non-NEC samples was marked by an abundance of Enterobacteriaceae and decreased diversity among NEC samples.The results indicate that NEC is a disease without a uniform pattern of microbial colonization, but that NEC is associated with an abundance of strict anaerobes and a decrease in community diversity.
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- 2014
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22. Innate Immune Signaling in the Pathogenesis of Necrotizing Enterocolitis
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David J. Hackam, Amin Afrazi, Misty Good, and Chhinder P. Sodhi
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host.
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- 2013
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23. Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors.
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Matthew D Neal, Hongpeng Jia, Benjamin Eyer, Misty Good, Christopher J Guerriero, Chhinder P Sodhi, Amin Afrazi, Thomas Prindle, Congrong Ma, Maria Branca, John Ozolek, Jeffrey L Brodsky, Peter Wipf, and David J Hackam
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Medicine ,Science - Abstract
Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases.
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- 2013
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24. Integrating longitudinal clinical and microbiome data to predict growth faltering in preterm infants.
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Jose Lugo-Martinez, Siwei Xu, Justine Levesque, Daniel Gallagher, Leslie A. Parker, Josef Neu, Christopher J. Stewart, Janet E. Berrington, Nicholas D. Embleton, Gregory Young, Katherine E. Gregory, Misty Good, Arti Tandon, David Genetti, Tracy Warren, and Ziv Bar-Joseph
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- 2022
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25. Intestinal epithelium in early life
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Lauren Frazer and Misty Good
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Immunology ,Immunology and Allergy - Published
- 2022
26. Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants with Necrotizing Enterocolitis
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Angela N. Lewis, Diomel de la Cruz, James L. Wynn, Lauren C. Frazer, William Yakah, Camilia R. Martin, Heeju Yang, Elena Itriago, Jana Unger, Amy B. Hair, Jessica Miele, Brynne A. Sullivan, Ameena Husain, and Misty Good
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Cohort Studies ,Enterocolitis, Necrotizing ,Organ Dysfunction Scores ,Pediatrics, Perinatology and Child Health ,Infant, Newborn ,Humans ,Infant ,Infant, Newborn, Diseases ,Infant, Premature ,Article ,Retrospective Studies ,Developmental Biology - Abstract
Introduction: The neonatal sequential organ failure assessment (nSOFA) score is a tool for calculating mortality risk of infants in the neonatal intensive care unit. The utility of the nSOFA in determining the risk of mortality or the association with surgical intervention among infants with necrotizing enterocolitis (NEC) has not been investigated. Methods: We performed a retrospective, cohort study of preterm (Results: Of the 259 infants, nSOFA scores for infants who died (n = 39) or had the composite outcome of surgery or death (n = 114) were significantly higher (p < 0.05) early in the NEC course compared to nSOFA scores for infants who survived medical NEC. Twelve hours after evaluation, the area under the receiver operating characteristic curve was 0.87 (95% confidence interval [CI], 0.80–0.93) to discriminate for mortality and 0.84 (95% CI, 0.79–0.90) for surgery or death (p < 0.001). A maximum nSOFA score of ≥4 at −6, 0, 6, or 12 h following evaluation was associated with a 20-fold increase in mortality and 19-fold increase in surgery or death compared with a score of p < 0.001). Conclusion: In this multicenter cohort, the nSOFA score was able to discriminate well for death as well as surgery or death among infants with NEC. The nSOFA is a clinical research tool that may be used in infants with NEC to improve classification by objective quantification of organ dysfunction.
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- 2022
27. Essentials of neonatal-perinatal medicine fellowship: innovations in medical education
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Deirdre O’Reilly, Rita Dadiz, Alison Falck, C Lydia Wraight, Sabrina K Malik, Susan Izatt, Patricia R. Chess, Brittany Schwarz, Jayasree Nair, Kris Reber, Maria Gillam-Krakauer, Kristen T. Leeman, Margarita M. Vasquez, Autumn Kiefer, Melissa Bauserman, Erin Cicalese, Taylor Sawyer, Patrick Myers, M. Cody Smith, Kate Stanley, Megan M. Gray, Misty Good, Robert M. Angert, Jennifer A. Wambach, Elizabeth M. Bonachea, Lindsay Johnston, Jennifer Trzaski, Jotishna Sharma, Melissa M. Carbajal, Allison H. Payne, Karena G. Lawrence, Sara K. Kane, Mackenzie S. Frost, Josephine Enciso, and Heather M. French
- Subjects
Medical education ,Quality management ,business.industry ,education ,MEDLINE ,Graduate medical education ,Obstetrics and Gynecology ,Population health ,Scholarship ,Pediatrics, Perinatology and Child Health ,Health care ,ComputingMilieux_COMPUTERSANDEDUCATION ,Medicine ,Virtual learning environment ,Neonatal perinatal medicine ,business - Abstract
Due to the changing complex healthcare environment, educational innovation is essential to meet the needs of current and future neonatal-perinatal medicine (NPM) leaders. Greater clinical demands, decreased academic funding, and expanded graduate medical education program requirements have negatively impacted time for teaching and educational scholarship potentially limiting innovation in the field. By focusing on adult learning principles, embracing technology, and promoting collaboration, today's educators are preparing the next generation of neonatologists. Current innovations include regionalizing simulation boot camps, leveraging virtual learning to increase accessibility, developing niche training opportunities, and incorporating population health principles within existing quality initiatives. Areas in need of additional innovation include faculty and fellow development for teaching skills, expansion of educational networks, and dissemination and financial support of educational scholarship. These efforts and future innovations will require medical institutions and national NPM organizations to further invest in the medical educator as part of their missions.
- Published
- 2021
28. Dilemmas in feeding infants with intestinal failure: a neonatologist’s perspective
- Author
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Amy Hair and Misty Good
- Subjects
Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology ,Article - Abstract
Intestinal failure in neonatal and pediatric populations can be debilitating for patients and difficult to manage for clinicians. Management strategies include referral to an intestinal rehabilitation center, small volume trophic feeds to stimulate the intestine with cautious advancement of enteral nutrition using a standardized and evidence-based feeding protocol, and supplemental parenteral nutrition to optimize an infant's growth and nutrition. In this review, we discuss the causes of intestinal failure, parenteral nutrition strategies, enteral feeding initiation and advancement protocols, as well as the challenges in feeding an infant with intestinal failure.
- Published
- 2022
29. Dilemmas in human milk fortification
- Author
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Amy B. Hair, Brian Scottoline, and Misty Good
- Subjects
Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology ,Article - Abstract
Fortification of human milk is the standard of care for very low birth weight (VLBW) infants and is required to support adequate postnatal growth and development. Achieving adequate growth velocity and preventing growth faltering is critical for the developing neonatal brain and optimizing long-term neurodevelopmental outcomes. Mother's milk is the gold standard nutrition to feed preterm infants, however, it does not provide the nutrients needed to support the growth of VLBW infants. After the decision is made to use mother's milk (if available) or alternatively, donor human milk, many dilemmas exist with regards to additional treatment decisions surrounding the type of fortification to use, when to fortify, and the duration of fortification. In this article, we will review the differences in mother's milk compared to donor milk, the different types of human milk fortifiers, the optimal timing of fortification, and discuss when to discontinue human milk fortification.
- Published
- 2022
30. Key Biologically Active Components of Breast Milk and their Beneficial Effects
- Author
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Laura N. Reniker, Lauren C. Frazer, and Misty Good
- Subjects
Pediatrics, Perinatology and Child Health ,Surgery - Published
- 2023
31. Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis
- Author
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Elizabeth Huang, Zerina Hodzic, Shay S. Bidani, P. K. Agrawal, Aiza Bustos, Qingqing Gong, Martin Goree, Jamie M. Rimer, Angela N. Lewis, Misty Good, Elise Hu, Lila S. Nolan, Wyatt E. Lanik, Jennifer K. Bando, Marie L. Laury, Victoria Liu, Sarah E. Gale, and Belgacem Mihi
- Subjects
Chemokine ,Indoles ,medicine.medical_treatment ,Interleukin-1beta ,Immunology ,Article ,Mice ,Downregulation and upregulation ,Enterocolitis, Necrotizing ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Humans ,Immunology and Allergy ,Intestinal Mucosa ,Scavenger receptor ,biology ,Macrophages ,Membrane Proteins ,General Medicine ,Dendritic cell ,Aryl hydrocarbon receptor ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Cytokine ,Animals, Newborn ,Receptors, Aryl Hydrocarbon ,Necrotizing enterocolitis ,biology.protein ,Cancer research ,Increased inflammatory response ,Signal Transduction - Abstract
Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4− monocyte–dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.
- Published
- 2021
32. Murine astrovirus tropism for goblet cells and enterocytes facilitates an IFN-λ response in vivo and in enteroid cultures
- Author
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Gowri Kalugotla, Harshad Ingle, Belgacem Mihi, Megan T. Baldridge, Misty Good, Michael S. Diamond, Rodney D. Newberry, Keely G. McDonald, Yuhao Li, Pritesh Desai, Sanghyun Lee, Ebrahim Hassan, Jana Gawron, Elizabeth A. Kennedy, and Heyde Makimaa
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Biology ,Article ,Microbiology ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Organ Culture Techniques ,Th2 Cells ,In vivo ,Astroviridae Infections ,medicine ,Immunology and Allergy ,Animals ,Humans ,Tropism ,Cells, Cultured ,Mice, Knockout ,Innate immune system ,Coinfection ,Intestinal epithelium ,Immunity, Innate ,Gastroenteritis ,Mice, Inbred C57BL ,Chronic infection ,Viral Tropism ,030104 developmental biology ,Cytokine ,Enterocytes ,Astroviridae ,Cytokines ,Goblet Cells ,Cellular Tropism ,030215 immunology - Abstract
Although they globally cause viral gastroenteritis in children, astroviruses are understudied due to the lack of well-defined animal models. While murine astroviruses (muAstVs) chronically infect immunodeficient mice, a culture system and understanding of their pathogenesis is lacking. Here, we describe a platform to cultivate muAstV using air–liquid interface (ALI) cultures derived from mouse enteroids, which support apical infection and release. Chronic muAstV infection occurs predominantly in the small intestine and correlates with higher interferon-lambda (IFN-λ) expression. MuAstV stimulates IFN-λ production in ALI, recapitulating our in vivo findings. We demonstrate that goblet cells and enterocytes are targets for chronic muAstV infection in vivo, and that infection is enhanced by parasite co-infection or type 2 cytokine signaling. Depletion of goblet cells from ALI limits muAstV infection in vitro. During chronic infection, muAstV stimulates IFN-λ production in infected cells and induces ISGs throughout the intestinal epithelium in an IFN-λ-receptor-dependent manner. Collectively, our study provides insights into the cellular tropism and innate immune responses to muAstV and establishes an enteroid-based culture system to propagate muAstV in vitro.
- Published
- 2021
33. Essentials of neonatal-perinatal medicine fellowship: scholarship perspective
- Author
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Misty Good, Margarita M. Vasquez, Melissa Bauserman, Patricia R. Chess, and Melissa M. Carbajal
- Subjects
education ,MEDLINE ,Article ,Competition (economics) ,Mentorship ,Pregnancy ,Physicians ,Humans ,Medicine ,Attrition ,Fellowships and Scholarships ,Neonatal perinatal medicine ,Child ,health care economics and organizations ,Medical education ,business.industry ,Pediatric research ,Perspective (graphical) ,Infant, Newborn ,Obstetrics and Gynecology ,medicine.disease ,humanities ,Scholarship ,Pediatrics, Perinatology and Child Health ,Female ,Neonatology ,business - Abstract
Neonatal-perinatal medicine fellows must achieve a meaningful accomplishment in scholarly activity as part of their training. Despite the requirement for scholarly training in fellowship, there is a vanishingly small number of MD-only physician-scientists pursuing a research-oriented career. Recent neonatal trainees have identified several factors that preclude their careers in research-focused academic neonatology, including lower pay in academic positions, inadequate training in research techniques, and the perception that individuals in research careers have a poor work-life balance. High competition for limited pediatric research funds also contributes to a diminishing pool of physician-scientists in neonatology. This small number of physician-scientists is threatened by a high rate of attrition among physicians who enter this career path. In order to prevent further declines in the number of neonatal physician-scientists, we need improvements in funding and strong intra- and cross-institutional mentorship to foster individuals interested in a career as a physician-scientist.
- Published
- 2021
34. Shaping infant development from the inside out: Bioactive factors in human milk
- Author
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Sarah F, Andres, Brian, Scottoline, and Misty, Good
- Subjects
Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology - Abstract
Human breast milk is the optimal nutrition for all infants and is comprised of many bioactive and immunomodulatory components. The components in human milk, such as probiotics, human milk oligosaccharides (HMOs), extracellular vesicles, peptides, immunoglobulins, growth factors, cytokines, and vitamins, play a critical role in guiding neonatal development beyond somatic growth. In this review, we will describe the bioactive factors in human milk and discuss how these factors shape neonatal immunity, the intestinal microbiome, intestinal development, and more from the inside out.
- Published
- 2023
35. Vaginal seeding after cesarean birth: Can we build a better infant microbiome?
- Author
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Jeannie Kelly, Misty Good, and Lila S. Nolan
- Subjects
medicine.medical_specialty ,Cesarean Section ,Obstetrics ,Microbiota ,Infant ,food and beverages ,General Medicine ,Biology ,Delivery mode ,Article ,female genital diseases and pregnancy complications ,surgical procedures, operative ,Cesarean Birth ,Pregnancy ,Vagina ,medicine ,Humans ,Female ,Seeding ,Microbiome ,Cesarean delivery ,reproductive and urinary physiology - Abstract
With over one-third of pregnancies in the United States being delivered by cesarean and the growing knowledge of morbidities associated with repeat cesarean deliveries, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Society for Maternal-Fetal Medicine, and the American College of Obstetricians and Gynecologists convened a workshop to address the concept of preventing the first cesarean. The available information on maternal and fetal factors, labor management and induction, and non-medical factors leading to the first cesarean were reviewed as well as the implications of the first cesarean on future reproductive health. Key points were identified to assist with reduction in cesarean rates including that labor induction should be performed primarily for medical indication; if done for non-medical indications, the gestational age should be at least 39 weeks or more and the cervix should be favorable, especially in the nulliparous patient. Review of the current literature demonstrates the importance of adhering to appropriate definitions for failed induction and arrest of labor progress. The diagnosis of “failed induction” should only be made after an adequate attempt. Adequate time for normal latent and active phases of the first stage, and for the second stage, should be allowed, as long as the maternal and fetal conditions permit. The adequate time for each of these stages appears to be longer than traditionally estimated. Operative vaginal delivery is an acceptable birth method when indicated, and can safely prevent cesarean delivery. Given the progressively declining use, it is critical that training and experience in operative vaginal delivery is facilitated and encouraged. When discussing the first cesarean with a patient, counseling should include its effect on future reproductive health.
- Published
- 2021
36. IL-17RA-signaling in Lgr5(+) intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment
- Author
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Xun Lin, Stephen J. Gaudino, Kyung Ku Jang, Tej Bahadur, Ankita Singh, Anirban Banerjee, Michael Beaupre, Timothy Chu, Hoi Tong Wong, Chang-Kyung Kim, Cody Kempen, Jordan Axelrad, Huakang Huang, Saba Khalid, Vyom Shah, Onur Eskiocak, Olivia B. Parks, Artan Berisha, Jeremy P. McAleer, Misty Good, Miko Hoshino, Richard Blumberg, Agnieszka B. Bialkowska, Sarah L. Gaffen, Jay K. Kolls, Vincent W. Yang, Semir Beyaz, Ken Cadwell, and Pawan Kumar
- Subjects
Mice, Knockout ,Receptors, Interleukin-17 ,Stem Cells ,Immunology ,Dextran Sulfate ,Interleukin-17 ,NF-kappa B ,Cell Differentiation ,SOX9 Transcription Factor ,Cell Communication ,Colitis ,Article ,Receptors, G-Protein-Coupled ,Intestines ,Mice ,Infectious Diseases ,Basic Helix-Loop-Helix Transcription Factors ,Immunology and Allergy ,Animals ,Humans ,Cell Lineage ,Intestinal Mucosa ,Signal Transduction - Abstract
The Th17 cell lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggestive of additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor Atoh1 in Lgr5(+) intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1(+) cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the crosstalk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.
- Published
- 2022
37. Opportunities for the federal government to advance necrotizing enterocolitis research
- Author
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Misty Good, Tonse N. K. Raju, Jennifer Canvasser, and Samir K. Gadepalli
- Subjects
Government ,MEDLINE ,medicine.disease ,digestive system diseases ,03 medical and health sciences ,0302 clinical medicine ,Nursing ,030225 pediatrics ,Political science ,Pediatrics, Perinatology and Child Health ,Necrotizing enterocolitis ,medicine ,Family engagement ,health care economics and organizations ,030217 neurology & neurosurgery - Abstract
Background Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in the neonatal ICU with minimal progress in the research. Methods Federal webpages were queried to look for funding opportunity announcements (FOAs) and to develop lists of funded projects on NEC to identify gaps in NEC-related research topics. Results Over the past 30 years, the National Institutes of Health (NIH) issued two FOAs to stimulate research on NEC with $4.1 million set aside for the first year of respective funding. We identified 23 recently funded studies of which 18 were research projects, 4 training grants, and 1 conference grant support. Only one grant focused on parent and family engagement in the NICU. Conclusion There are significant research gaps that can be addressed with adequate funding from the federal government on the prevention and treatment of NEC.
- Published
- 2020
38. Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis
- Author
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Rodney D. Newberry, Kathryn A. Knoop, Nurmohammad Shaikh, Misty Good, Alexandria N. Floyd, Phillip I. Tarr, Brigida Rusconi, Barbara B. Warner, Paige E. Coughlin, I. Malick Ndao, Marilyn B. Escobedo, Carla Hall-Moore, and Andrew J. Gasparrini
- Subjects
Multidisciplinary ,biology ,Neonatal sepsis ,Chromosomal translocation ,medicine.disease ,medicine.disease_cause ,biology.organism_classification ,Intestinal epithelium ,Microbiology ,Sepsis ,Epidermal growth factor ,Pathogenic Escherichia coli ,medicine ,Escherichia coli ,Pathogen - Abstract
Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients’ intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen Escherichia coli , which spreads systemically and caused a rapid, fatal disease in pups. Translocation of Escherichia coli was associated with the formation of colonic goblet cell-associated antigen passages (GAPs), which translocate enteric bacteria across the intestinal epithelium. Thus, maternally derived EGF, and potentially other EGFR ligands, prevents dissemination of a gut-resident pathogen by inhibiting goblet cell-mediated bacterial translocation. Through manipulation of maternally derived EGF and alteration of the earliest gut defenses, we have developed an animal model of pathogen dissemination which recapitulates gut-origin neonatal LOS.
- Published
- 2020
39. Are surgeons behind the scientific eight ball: Delayed acquisition of the NIH K08 mentored career development award
- Author
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Kristen M. Seiler, Brian D. Hosfield, Troy A. Markel, Misty Good, Gary L. Dunnington, and Quincy E. John
- Subjects
Male ,Biomedical Research ,Time Factors ,Databases, Factual ,education ,Awards and Prizes ,Pediatrics ,Risk Assessment ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal Medicine ,Humans ,Medicine ,030212 general & internal medicine ,health care economics and organizations ,Disadvantage ,Medical education ,Career Choice ,business.industry ,Mentors ,General Medicine ,Achievement ,United States ,Career Mobility ,Education, Medical, Graduate ,General Surgery ,030220 oncology & carcinogenesis ,Clinical training ,Health Resources ,Female ,Surgery ,Clinical Competence ,business ,Career development - Abstract
BACKGROUND: Surgery residents complete their research training early in residency. Non-surgical trainees typically have research incorporated toward the last two years of their fellowship, conferring an advantage to apply for grants with recent research experience and preliminary data. METHODS: The NIH RePORTER database was queried for K08 awardees trained in medicine, pediatrics, and surgery from 2013–2017. 406 K08 recipients were identified and time from completion of clinical training to achieving a K08 award was measured. Data were compared using ANOVA and expressed as mean. P
- Published
- 2020
40. Dithizone-induced Paneth cell disruption significantly decreases intestinal perfusion in the murine small intestine
- Author
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Jennifer N. Berger, Misty Good, Steven J. McElroy, and Huyiu Gong
- Subjects
Small ,Pediatrics ,Intestinal microvasculature ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Necrotizing enterocolitis ,Ischemia ,Intestine, Small ,Diphtheria Toxin ,Pediatric ,General Medicine ,Intestine ,medicine.anatomical_structure ,Dithizone ,030220 oncology & carcinogenesis ,medicine.symptom ,Perfusion ,Biotechnology ,Signal Transduction ,Paneth Cells ,Nitric Oxide ,Article ,Nitric oxide ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Enterocolitis, Necrotizing ,030225 pediatrics ,medicine ,Animals ,Animal model ,Diphtheria toxin ,Enterocolitis ,Animal ,business.industry ,Microcirculation ,Perinatal Period - Conditions Originating in Perinatal Period ,medicine.disease ,Molecular biology ,Small intestine ,Disease Models, Animal ,chemistry ,Disease Models ,Pediatrics, Perinatology and Child Health ,Paneth cell ,Surgery ,Necrotizing ,Digestive Diseases ,business ,Vasoconstriction - Abstract
PurposeNecrotizing enterocolitis is associated with decreased intestinal perfusion and ischemia. Paneth cells, specialized epithelial cells, have been shown to regulate the intestinal vasculature and disruption of these cells has been associated with NEC. We hypothesized that Paneth cell disruption in immature mice intestine would decrease the perfusion of the intestinal microvasculature.MethodsPaneth cells were disrupted in P14-16 mice using chemical (dithizone) and transgenic (diphtheria toxin) methodology. Six hours after Paneth cell disruption, Dylight 488 was injected directly into the left ventricle and allowed to perfuse for 5 minutes prior to intestinal harvesting. Tissue samples were evaluated with confocal fluorescence microscopy to quantify intestinal perfusion and samples were quantified by real time RT-PCR for gene expression.ResultsDithizone treatment significantly decreased intestinal perfusion compared to controls (p 0.21). Intestines from all treatment groups had similar PECAM staining, but intestines treated with dithizone had significantly decreased nNOS and iNOS gene expression compared to controls (p
- Published
- 2019
41. Selective hypermethylation is evident in small intestine samples from infants with necrotizing enterocolitis
- Author
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Misty Good, Tianjiao Chu, Patricia Shaw, Lila S. Nolan, Joseph Wrobleski, Carlos Castro, Qingqing Gong, Olivia DeWitt, David N. Finegold, and David Peters
- Subjects
Infant, Newborn ,Infant ,DNA Methylation ,digestive system diseases ,Infant, Newborn, Diseases ,Enterocolitis, Necrotizing ,Intestine, Small ,Genetics ,Humans ,CpG Islands ,Molecular Biology ,Genetics (clinical) ,Infant, Premature ,Developmental Biology - Abstract
Objective Necrotizing enterocolitis (NEC) is the most common and lethal gastrointestinal disease affecting preterm infants. NEC develops suddenly and is characterized by gut barrier destruction, an inflammatory response, intestinal necrosis and multi-system organ failure. There is currently no method for early NEC detection, and the pathogenesis of NEC remains unclear. Design To further understand the molecular mechanisms that support NEC, we used solution phase hybridization and next-generation DNA sequencing of bisulfite converted DNA to perform targeted genome-wide analysis of DNA methylation at high read depth. Results We found that ileal samples from surgical NEC infants (n = 5) exist in a broadly hypermethylated state relative to their non-NEC counterparts (n = 9). These trends were not uniform, with hypermethylation being most consistently observed outside CpG islands and promoters. We further identified several biologically interesting gene promoters that displayed differential methylation in NEC and a number of biological pathways that appear dysregulated in NEC. We also found that DNA methylation patterns identified in ileal NEC tissue were correlated with those found and published previously in stool samples from NEC-affected infants. Conclusion We confirmed that surgical NEC is associated with broad DNA hypermethylation in the ileum, and this may be detectable in stool samples of affected individuals. Thus, an epigenomic liquid biopsy of stool may have significant potential as a biomarker with respect to the diagnostic/predictive detection of NEC. Our findings, along with recent similar observations in colon, suggest that epigenomic dysregulation is a significant feature of surgical NEC. These findings motivate future studies which will involve the longitudinal screening of samples obtained prior to the onset of NEC. Our long-term goal is the development of novel screening, diagnostic and phenotyping methods for NEC.
- Published
- 2021
42. A protocol for the induction of experimental necrotizing enterocolitis in neonatal mice
- Author
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Misty Good, Heather N. Hofmeister, Qingqing Gong, and Lila S. Nolan
- Subjects
Lipopolysaccharides ,Science (General) ,ved/biology.organism_classification_rank.species ,Enteric bacteria ,Biology ,Bioinformatics ,Microbiology ,General Biochemistry, Genetics and Molecular Biology ,Q1-390 ,Feces ,Mice ,Model Organisms ,In vivo ,Enterocolitis, Necrotizing ,Ileum ,Developmental biology ,Health Sciences ,medicine ,Protocol ,Animals ,Model organism ,Hypoxia ,Molecular Biology ,General Immunology and Microbiology ,ved/biology ,General Neuroscience ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,Animals, Newborn ,Necrotizing enterocolitis - Abstract
Summary Recapitulating human NEC using animal models has been insightful in dissecting the signaling pathways, immune-mediated mechanisms, genetic signatures, and the intestinal architecture of NEC. This protocol describes an in vivo murine NEC model, using hypoxia and formula containing lipopolysaccharide and enteric bacteria derived from an infant with NEC. With this mouse model, we aim to further dissect NEC pathogenesis and develop new therapeutic strategies. For complete details on the use and execution of this protocol, please refer to Mihi et al. (2021)., Graphical abstract, Highlights • This protocol describes the induction of murine necrotizing enterocolitis (NEC) • This mouse model is based on the use of hypoxia and formula supplemented with LPS • This mouse model can be used to study NEC pathogenesis and therapeutic targets, Recapitulating human NEC using animal models has been insightful in dissecting the signaling pathways, immune-mediated mechanisms, genetic signatures, and the intestinal architecture of NEC. This protocol describes an in vivo murine NEC model, using hypoxia and formula containing lipopolysaccharide and enteric bacteria derived from an infant with NEC. With this mouse model, we aim to further dissect NEC pathogenesis and develop new therapeutic strategies.
- Published
- 2021
43. Untargeted Metabolomic Analysis of Human Milk from Mothers of Preterm Infants
- Author
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Olivia N. DeWitt, Qingqing Gong, Misty Good, Lila S. Nolan, James J. Sollome, Angela N. Lewis, and Robert D. Williams
- Subjects
Male ,medicine.medical_specialty ,Birth weight ,Mothers ,Oligosaccharides ,Physiology ,Breast milk ,Article ,chemistry.chemical_compound ,Metabolomics ,newborn ,Metabolome ,Birth Weight ,Humans ,Medicine ,TX341-641 ,Neonatology ,Amino Acids ,metabolites ,Principal Component Analysis ,Nutrition and Dietetics ,necrotizing enterocolitis ,Milk, Human ,Fatty acid metabolism ,Nutrition. Foods and food supply ,business.industry ,Fatty Acids ,Significant difference ,prematurity ,Infant, Newborn ,human milk ,Amino Sugars ,medicine.disease ,metabolomics ,digestive system diseases ,Oxidative Stress ,chemistry ,Multivariate Analysis ,Necrotizing enterocolitis ,breast milk ,Female ,Energy Metabolism ,business ,Glycolysis ,Infant, Premature ,Food Science - Abstract
The application of metabolomics in neonatology offers an approach to investigate the complex relationship between nutrition and infant health. Characterization of the metabolome of human milk enables an investigation into nutrients that affect the neonatal metabolism and identification of dietary interventions for infants at risk of diseases such as necrotizing enterocolitis (NEC). In this study, we aimed to identify differences in the metabolome of breast milk of 48 mothers with preterm infants with NEC and non-NEC healthy controls. A minimum significant difference was observed in the human milk metabolome between the mothers of infants with NEC and mothers of healthy control infants. However, significant differences in the metabolome related to fatty acid metabolism, oligosaccharides, amino sugars, amino acids, vitamins and oxidative stress-related metabolites were observed when comparing milk from mothers with control infants of ≤1.0 kg birth weight and >, 1.5 kg birth weight. Understanding the functional biological features of mothers’ milk that may modulate infant health is important in the future of tailored nutrition and care of the preterm newborn.
- Published
- 2021
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44. A Promising Genetic Target for a Deadly Disease: Single Immunoglobulin Interleukin 1 (SIGIRR) Mutations in Necrotizing Enterocolitis
- Author
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Camilia R. Martin and Misty Good
- Subjects
Hepatology ,business.industry ,Necrotizing enterocolitis ,Immunology ,Gastroenterology ,Medicine ,Disease ,RC799-869 ,Diseases of the digestive system. Gastroenterology ,business ,medicine.disease - Published
- 2022
45. Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice
- Author
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Cristina Lupu, Robert Silasi, Girija Regmi, Ravi S. Keshari, Kathryn Burge, Misty Good, Florea Lupu, Majoi A. Trammell, Hala Chaaban, Steven J. McElroy, Jeffrey Eckert, and David W. Dyer
- Subjects
0301 basic medicine ,Small ,Mice ,0302 clinical medicine ,Intestine, Small ,2.1 Biological and endogenous factors ,TX341-641 ,Intestinal Mucosa ,Hyaluronic Acid ,Pediatric ,Nutrition and Dietetics ,Cell Differentiation ,Intestine ,Intestines ,medicine.anatomical_structure ,Goblet Cells ,Pediatric Research Initiative ,Paneth Cells ,1.1 Normal biological development and functioning ,Crypt ,Biology ,digestive system ,Article ,Microbiology ,hyaluronan ,03 medical and health sciences ,Food Sciences ,Downregulation and upregulation ,medicine ,Animals ,Microbiome ,preterm infants ,Nutrition ,Cell Proliferation ,Goblet cell ,necrotizing enterocolitis ,human milk bioactive factors ,Nutrition. Foods and food supply ,Cell growth ,Lachnospiraceae ,Perinatal Period - Conditions Originating in Perinatal Period ,Newborn ,Small intestine ,Gastrointestinal Microbiome ,intestinal barrier ,030104 developmental biology ,Animals, Newborn ,Dietary Supplements ,Colostrum ,Digestive Diseases ,prebiotics ,030217 neurology & neurosurgery ,Food Science - Abstract
The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota, the implications of these responses need to be determined.
- Published
- 2021
46. Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration
- Author
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Victoria Liu, Angela N. Lewis, Lila S. Nolan, Elizabeth Huang, Qingqing Gong, Misty Good, P. K. Agrawal, Martin Goree, Pawan Kumar, Olivia B. Parks, Jamie M. Rimer, Cliff J. Luke, Wyatt E. Lanik, Belgacem Mihi, Elise Hu, Sarah E. Gale, Shay S. Bidani, Jay K. Kolls, and Marie L. Laury
- Subjects
Medicine (General) ,Chemokine CXCL1 ,Chemokine CXCL2 ,Interleukin-1beta ,microbiome ,Inflammation ,Weaning ,intestinal immunity ,General Biochemistry, Genetics and Molecular Biology ,Infant, Newborn, Diseases ,Interleukin 22 ,Mice ,R5-920 ,Enterocolitis, Necrotizing ,Medicine ,Animals ,Humans ,Protein Isoforms ,Intestinal Mucosa ,Receptor ,Mice, Knockout ,necrotizing enterocolitis ,business.industry ,Regeneration (biology) ,Interleukins ,interleukin-22 ,Infant, Newborn ,Interleukin ,Gene Expression Regulation, Developmental ,Receptors, Interleukin ,medicine.disease ,Preview ,Epithelium ,Recombinant Proteins ,digestive system diseases ,epithelial cells ,Gastrointestinal Microbiome ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,regeneration ,Necrotizing enterocolitis ,Immunology ,medicine.symptom ,business ,Homeostasis ,Infant, Premature ,Signal Transduction - Abstract
Necrotizing enterocolitis (NEC) is an intestinal disorder that disproportionately affects premature infants and lacks in effective therapeutics. Mihi and colleagues1 demonstrated that the cytokine interleukin-22 promotes intestinal epithelial regeneration and reduces disease severity in an experimental model of NEC., Necrotizing enterocolitis (NEC) is an intestinal disorder that disproportionately affects premature infants and lacks in effective therapeutics. Mihi and colleagues demonstrated that the cytokine interleukin-22 promotes intestinal epithelial regeneration and reduces disease severity in an experimental model of NEC.
- Published
- 2021
47. Neonatal necrotizing enterocolitis-associated DNA methylation signatures in the colon are evident in stool samples of affected individuals
- Author
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Austin Chamberlain, Laura Linneman, David G. Peters, Lila S. Nolan, Qingqing Gong, Lora McClain, Krista Cooksey, Patricia Shaw, Carlos A. Castro, Tianjiao Chu, Olivia N. DeWitt, Misty Good, and David N. Finegold
- Subjects
0301 basic medicine ,Epigenomics ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Short Communication ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,Feces ,0302 clinical medicine ,Enterocolitis, Necrotizing ,Genetics ,medicine ,Humans ,Epigenetics ,Gene Expression Profiling ,Infant, Newborn ,Infant ,Methylation ,Sequence Analysis, DNA ,DNA Methylation ,medicine.disease ,digestive system diseases ,030104 developmental biology ,CpG site ,Gene Expression Regulation ,Gastrointestinal disease ,Necrotizing enterocolitis ,DNA methylation ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,CpG Islands ,Female ,Disease Susceptibility ,Biomarkers ,Genome-Wide Association Study ,Signal Transduction - Abstract
Aim: Neonatal necrotizing enterocolitis (NEC) is a deadly and unpredictable gastrointestinal disease, for which no biomarker exists. We aimed to describe the methylation patterns in stool and colon from infants with NEC. Methods: We performed a high-resolution genome-wide epigenomic analysis using solution-phase hybridization and next-generation sequencing of bisulfite-converted DNA. Results: Our data reveal significant genomic hypermethylation in NEC tissues compared with non-NEC controls. These changes were more pronounced in regions outside CpG islands and gene regulatory elements, suggesting that NEC-specific hypermethylation is not a nonspecific global phenomenon. Conclusions: This study provides evidence of a methylomic signature associated with NEC that is detectable noninvasively and provides a new opportunity for the development of a novel diagnostic method for NEC.
- Published
- 2021
48. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants
- Author
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Michael J. Morowitz, Junyi Ji, Timothy W. Hand, Kathyayini P. Gopalakrishna, Justin T. Tometich, Benjamin R Macadangdang, Ansen H.P. Burr, Robyn Baker, Misty Good, Brian Firek, Congrong Ma, and Matthew B. Rogers
- Subjects
0301 basic medicine ,IgA binding ,Immunoglobulin A ,Adult ,Male ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Enterobacteriaceae ,Pregnancy ,Enterocolitis, Necrotizing ,Medicine ,Animals ,Humans ,Microbiome ,Child ,Immunity, Mucosal ,Enterocolitis ,biology ,Host Microbial Interactions ,business.industry ,Microbiota ,Infant, Newborn ,Infant ,General Medicine ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,030104 developmental biology ,Mucosal immunology ,030220 oncology & carcinogenesis ,Child, Preschool ,Necrotizing enterocolitis ,Immunology ,biology.protein ,Female ,Antibody ,medicine.symptom ,business ,Infant, Premature - Abstract
Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota1–3. The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear4–6. Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host–microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC. Immunoglobulin A antibodies in maternal milk are required for prevention of necrotizing enterocolitis in preterm neonates.
- Published
- 2019
49. Impact of Toll-Like Receptor 4 Signaling in Necrotizing Enterocolitis
- Author
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Belgacem Mihi Dvm and Misty Good Ms
- Subjects
03 medical and health sciences ,0302 clinical medicine ,Stereochemistry ,business.industry ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology ,Medicine ,030212 general & internal medicine ,State (functional analysis) ,business - Published
- 2019
50. Anti-severe acute respiratory syndrome coronavirus 2 antibodies induced in breast milk after Pfizer-BioNTech/BNT162b2 vaccination
- Author
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Jeannie Kelly, Misty Good, Nandini Raghuraman, Angela N. Lewis, Qingqing Gong, Lila S. Nolan, and Ebony B. Carter
- Subjects
Adult ,2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,biology ,Milk, Human ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Obstetrics and Gynecology ,Breast milk ,Antibodies, Viral ,Virology ,Vaccination ,biology.protein ,Research Letter ,Medicine ,Humans ,Female ,Antibody ,business ,BNT162 Vaccine - Published
- 2021
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