Center for Translational Research
Center for Translational Research
News Article | May 16, 2017
CHICAGO --- The brave new world of 3-D printed organs now includes implanted ovary structures that, true to their design, actually ovulate, according to a study by Northwestern University Feinberg School of Medicine and McCormick School of Engineering. By removing a female mouse's ovary and replacing it with a bioprosthetic ovary, the mouse was able to not only ovulate but also give birth to healthy pups. The moms were even able to nurse their young. The bioprosthetic ovaries are constructed of 3-D printed scaffolds that house immature eggs, and have been successful in boosting hormone production and restoring fertility in mice, which was the ultimate goal of the research. "This research shows these bioprosthetic ovaries have long-term, durable function," said Teresa K. Woodruff, a reproductive scientist and director of the Women's Health Research Institute at Feinberg. "Using bioengineering, instead of transplanting from a cadaver, to create organ structures that function and restore the health of that tissue for that person, is the holy grail of bioengineering for regenerative medicine." The paper will be published May 16 in Nature Communications. How is this research different from other 3-D printed structures? What sets this research apart from other labs is the architecture of the scaffold and the material, or "ink," the scientists are using, said Ramille Shah, assistant professor of materials science and engineering at McCormick and of surgery at Feinberg. That material is gelatin, which is a biological hydrogel made from broken-down collagen that is safe to use in humans. The scientists knew that whatever scaffold they created needed to be made of organic materials that were rigid enough to be handled during surgery and porous enough to naturally interact with the mouse's body tissues. "Most hydrogels are very weak, since they're made up of mostly water, and will often collapse on themselves," Shah said. "But we found a gelatin temperature that allows it to be self-supporting, not collapse, and lead to building multiple layers. No one else has been able to print gelatin with such well-defined and self-supported geometry." That geometry directly links to whether or not the ovarian follicles, organized hormone-producing support cells surrounding an immature egg cell, will survive in the ovary, which was one of the bigger findings in the study. "This is the first study that demonstrates that scaffold architecture makes a difference in follicle survival," Shah said. "We wouldn't be able to do that if we didn't use a 3-D printer platform." How does this impact humans? The scientists' sole objective for developing the bioprosthetic ovaries was to help restore fertility and hormone production in women who have undergone adult cancer treatments or those who survived childhood cancer and now have increased risks of infertility and hormone-based developmental issues. "What happens with some of our cancer patients is that their ovaries don't function at a high enough level and they need to use hormone replacement therapies in order to trigger puberty," said Monica Laronda, co-lead author of this research and a former post-doctoral fellow in the Woodruff lab. "The purpose of this scaffold is to recapitulate how an ovary would function. We're thinking big picture, meaning every stage of the girl's life, so puberty through adulthood to a natural menopause." Laronda is now an assistant professor at the Stanley Manne Children's Research Institute at the Ann & Robert H. Lurie Children's Hospital. Additionally, the successful creation of 3-D printed implants to replace complex soft tissue could significantly impact future work in soft tissue regenerative medicine. 3-D printing an ovary structure is similar to a child using Lincoln Logs, said Alexandra Rutz, co-lead author of the study and a former biomedical engineering graduate fellow in Shah's Tissue Engineering and Additive Manufacturing (TEAM) lab at the Simpson Querrey Institute. Children can lay the logs at right angles to form structures. Depending on the distance between the logs, the structure changes to build a window or a door, etc. "3-D printing is done by depositing filaments," said Rutz, who is now a Whitaker International Postdoctoral Scholar at École Des Mines De Saint-Étienne in Gardanne, France. "You can control the distance between those filaments, as well as the advancing angle between layers, and that would give us different pore sizes and different pore geometries." In Northwestern's lab, the researchers call these 3-D printed structures "scaffolds," and liken them to the scaffolding that temporarily surrounds a building while it undergoes repairs. "Every organ has a skeleton," said Woodruff, who also is the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "We learned what that ovary skeleton looked like and used it as model for the bioprosthetic ovary implant." In a building, the scaffolding supports the materials needed to repair the building until it's eventually removed. What's left is a structure capable of holding itself up. Similarly, the 3-D printed "scaffold" or "skeleton" is implanted into a female and its pores can be used to optimize how follicles, or immature eggs, get wedged within the scaffold. The scaffold supports the survival of the mouse's immature egg cells and the cells that produce hormones to boost production. The open structure also allows room for the egg cells to mature and ovulate, as well as blood vessels to form within the implant enabling the hormones to circulate within the mouse bloodstream and trigger lactation after giving birth. The all-female McCormick-Feinberg collaboration for this research was "very fruitful," Shah said, adding that it was motivational to be part of an all-female team doing research towards finding solutions to female health issues. "What really makes a collaboration work are the personalities and being able to find the humor in the research," Shah said. "Teresa and I joked that we're grandparents of these pups." This work was supported by the Northwestern University Watkins Chair of Obstetrics and Gynecology; the National Institutes of Health (NIH) National Center for Translational Research in Reproduction and Infertility (NCTRI); grant P50HD076188 from the Center for Reproductive Health After Disease; grant UH3TR001207 from the National Center for Advancing Translational Sciences (NCATS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Office of Women's Health Research (ORWH), and NIH Common Fund; grant 1K01DK099454-01 from the NIH; the Burroughs Welcome Fund Career Award at the Scienti?c Interface; and grant DGE-1324585 from the National Science Foundation Graduate Research Fellowship Program. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by grant P50-HD28934 from the NICHD/NIH (NCTRI). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work made use of the EPIC facility of the NUANCE Center at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN.
Budimirovic D.B.,Kennedy Krieger Institute |
Berry-Kravis E.,Rush University Medical Center |
Erickson C.A.,University of Cincinnati |
Hall S.S.,Stanford University |
And 7 more authors.
Journal of Neurodevelopmental Disorders | Year: 2017
Objective: Fragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS. Methods: After performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)'s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes. Results: To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures. Conclusion: Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials. © 2017 The Author(s).
PubMed | George Washington University and Center for Translational Research
Type: | Journal: Hospital pediatrics | Year: 2016
Health care disparities have been described for children of limited English-proficient (LEP) families compared with children of English-proficient (EP) families. Poor communication with the medical team may contribute to these worse health outcomes. Previous studies exploring communication in the PICU have excluded LEP families. We aimed to understand communication experiences and preferences in the 3 primary communication settings in the PICU. We also explored LEP families views on interpreter use in the PICU.EP and Spanish-speaking LEP families of children admitted to the PICU of a large tertiary pediatric hospital completed surveys between 24 hours and 7 days of admission.A total of 161 of 184 families were surveyed (88% response rate); 52 were LEP and 109 EP. LEP families were less likely to understand the material discussed on rounds (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.11-0.90), to report that PICU nurses spent enough time speaking with them (OR 0.15, 95% CI 0.05-0.41), and to report they could rely on their nurses for medical updates (OR 0.07, 95% CI 0.02-0.25) controlling for covariates, such as education, insurance type, presence of a chronic condition, PICU length of stay, and mortality index. LEP families reported 53% of physicians and 41% of nurses used an interpreter often.Physician and nurse communication with LEP families is suboptimal. Communication with LEP families may be improved with regular use of interpreters and an increased awareness of the added barrier of language proficiency.
Sharma. A.,U.S. National Institute on Aging |
Berga-Bolanos. R.,Center for Translational Research |
Sen J.M.,U.S. National Institute on Aging |
Alberola-Ila J.,Oklahoma Medical Research Foundation
PLoS ONE | Year: 2014
Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) Vα14-Jα18 gene. Temporal regulation and late appearance of Vα14-Jα18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR Vα14-Jα18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits Va14-Ja18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of RORγt, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo.
Baker J.N.,St Jude Childrens Research Hospital |
Levine D.R.,St Jude Childrens Research Hospital |
Hinds P.S.,Center for Translational Research |
Weaver M.S.,St Jude Childrens Research Hospital |
And 11 more authors.
Journal of Pediatrics | Year: 2015
Objective To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda. Study design A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus. Results A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate [RR]). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education. Conclusions This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families. © 2015 Elsevier Inc.
PubMed | Akron Children’s Hospital, University of Texas at Austin, Mercy Hospital Center and Clinics, Dana-Farber Cancer Institute and 5 more.
Type: Journal Article | Journal: The Journal of pediatrics | Year: 2015
To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda.A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus.A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate [RR]). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education.This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families.
Marino N.,U.S. National Cancer Institute |
Marshall J.-C.,U.S. National Cancer Institute |
Marshall J.-C.,Center for Translational Research |
Collins J.W.,U.S. National Cancer Institute |
And 4 more authors.
Cancer Research | Year: 2013
Nm23-H1 has been identified as a metastasis suppressor gene, but its protein interactions have yet to be understood with any mechanistic clarity. In this study, we evaluated the proteomic spectrum of interactions made by Nm23-H1 in 4T1 murine breast cancer cells derived from tissue culture, primary mammary tumors, and pulmonary metastases. By this approach, we identified the actin-severing protein Gelsolin as binding partner for Nm23-H1, verifying their interaction by coimmunoprecipitation in 4T1 cells as well as in human MCF7, MDA-MB-231T, and MDA-MB-435 breast cancer cells. In Gelsolin-transfected cells, coexpression of Nm23-H1 abrogated the actin-severing activity of Gelsolin. Conversely, actin severing by Gelsolin was abrogated by RNA interference- mediated silencing of endogenous Nm23-H1. Tumor cell motility was negatively affected in parallel with Gelsolin activity, suggesting that Nm23-H1 binding inactivated the actin-depolymerizing function of Gelsolin to inhibit cell motility. Using indirect immunoflourescence to monitor complexes formed by Gelsolin and Nm23-H1 in living cells, we observed their colocalization in a perinuclear cytoplasmic compartment that was associated with the presence of disrupted actin stress fibers. In vivo analyses revealed that Gelsolin overexpression increased the metastasis of orthotopically implanted 4T1 or tail vein-injected MDA-MB-231T cells (P = 0.001 and 0.04, respectively), along with the proportion of mice with diffuse liver metastases, an effect ablated by coexpression of Nm23-H1. We observed no variation in proliferation among lung metastases. Our findings suggest a new actin-based mechanism that can suppress tumor metastasis. © 2013 American Association for Cancer Research.
Urtasun R.,Mount Sinai School of Medicine |
Urtasun R.,Center for Translational Research |
Cubero F.J.,Mount Sinai School of Medicine |
Cubero F.J.,RWTH Aachen |
Nieto N.,Mount Sinai School of Medicine
Alcoholism: Clinical and Experimental Research | Year: 2012
Background: Induction of reactive oxygen species (ROS) is a central mechanism in alcohol hepatotoxicity. Krüppel-like factor 6 (KLF6), a transcription factor and a tumor-suppressor gene, is an early-responsive gene to injury; however, the effect of ROS and alcohol on KLF6 induction is unknown. The aim of this study is to investigate the contribution of 2 sources of ROS, cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase (NQO1), and alcohol on the modulation of KLF6Full expression, splicing to KLF6_V1 and KLF6_V2, and the effect on TNFα, a downstream target. Methods and Results: Endogenous ROS production in CYP2E1-expressing HepG2 cells induced mRNA and protein expression of KLF6Full and its splice variants compared to control cells. Incubation with pro-oxidants such as arachidonic acid (AA), β-naphtoflavone, and H2O2 further enhanced KLF6Full and its splice variants. The AA effects on KLF6Full and its splice forms were blocked by vitamin E-which prevents lipid peroxidation-and by diallylsulfide-a CYP2E1 inhibitor. Menadione and paraquat, 2 pro-oxidants metabolized via NQO1, induced KLF6Full mRNA in a thiol-dependent manner. Antioxidants and an NQO1 inhibitor suppressed the menadione-dependent increase in KLF6Full and its splice variants mRNA. Furthermore, primary hepatocytes and livers from chronic alcohol-fed rats, with elevated lipid peroxidation, H2O2 and CYP2E1 but with low GSH, showed a ~2-fold increase in KLF6Full mRNA compared to controls. Inhibition of p38 phosphorylation further up-regulated the CYP2E1 and the AA effects on KLF6Full mRNA, whereas inhibition JNK and ERK1/2 phosphorylation decreased both. KLF6_V1 but not KLF6Full ablation markedly increased TNFα levels in macrophages; thus, TNFα emerges as a downstream target of KLF6_V1. Conclusions: The novel effect of ROS on modulating KLF6Full expression and its splice variants could play a relevant role in liver injury and in TNFα regulation. © 2012 by the Research Society on Alcoholism.
Duan L.,Rush University Medical Center |
Danzer B.,Rush University Medical Center |
Levenson V.V.,Rush University Medical Center |
Levenson V.V.,Center for Translational Research |
Maki C.G.,Rush University Medical Center
Cancer Letters | Year: 2014
Autophagy is a mechanism of tamoxifen (TAM) resistance in ER-positive (ER+) breast cancer cells. In this study, we showed in ER+ MCF7 cells that 4-hydroxytamoxifen (4OHTAM) induced cellular nitric oxide (NO) that negatively regulates cellular superoxide (O2-) and cytotoxicity. 4OHTAM stimulated LC3 lipidation and formation of monodansylcadaverine (MDC)-labeled autophagic vesicles dependent on O2-. Depletion of NO increased O2- and LC3 lipidation, yet reduced formation of MDC-labeled autophagic vesicles. Instead, NO-depleted cells formed remarkably large vacuoles with rims decorated by LC3. The vacuoles were not labeled by MDC or the acidic lysosome-specific fluorescence dye acridine orange (AO). The vacuoles were increased by the late stage autophagy inhibitor chloroquine, which also increased LC3 lipidation. These results suggest NO is required for proper autophagic vesicle formation or maturation at a step after LC3 lipidation. In addition, 4OHTAM induced O2--dependent activation of ERK, inhibition of which destabilized lysosomes/autolysosomes upon 4OHTAM treatment and together with depletion of NO led to necrotic cell death. These results suggest an essential role for endogenous NO and ERK activation in the completion of pro-survival autophagy. © 2014 Elsevier Ireland Ltd.
PubMed | Center for Translational Research
Type: Review | Journal: Current neurology and neuroscience reports | Year: 2016
Increasing knowledge on genetic etiology of pediatric neurologic disorders is affecting the practice of the specialty. I reviewed here the history of pediatric neurologic disorder classification and the role of genetics in the process. I also discussed the concept of clinical neurogenetics, with its role in clinical practice, education, and research. Finally, I propose a flexible model for clinical neurogenetics in child neurology in the twenty-first century. In combination with disorder-specific clinical programs, clinical neurogenetics can become a home for complex clinical issues, repository of genetic diagnostic advances, educational resource, and research engine in child neurology.