Publications by authors named "Kyle Lewis"

34 Publications

Lamotrigine and Stevens-Johnson Syndrome Prevention.

Psychopharmacol Bull 2021 Mar;51(2):96-114

Edinoff, MD, Nguyen, MD, Gerald, MD, Louisiana State University Health Science Center Shreveport, Department of Psychiatry and Behavioral Medicine, Shreveport, LA. Crane, BS, Lewis, BS, St Pierre, BS, Louisiana State University Shreveport School of Medicine, Shreveport, LA. Alan D. Kaye, MD, PhD, Louisiana State University New Orleans, Department of Anesthesiology, New Orleans, LA, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA. Gennuso, MD, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA. Adam M. Kaye, PharmD, Jessica S. Kaye, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Department of Pharmacy Practice, Stockton, CA. Rachel J. Kaye, BA, Medical College of South Carolina, Charleston, SC. Varrassi, MD, PhD, FIPP, Paolo Procacci Foundation, Via Tacito 7, Roma, Italy. Viswanath, MD, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, Creighton University School of Medicine, Department of Anesthesiology, Omaha, NE, Valley Anesthesiology and Pain Consultants-Envision Physician Services, Phoenix, AZ. Urits, MD, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA, Southcoast Health, Southcoast Physicians Group Pain Medicine, Wareham, MA.

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related-common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146560PMC
March 2021

STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.

Nat Commun 2021 06 3;12(1):3299. Epub 2021 Jun 3.

Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada.

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.
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http://dx.doi.org/10.1038/s41467-021-23396-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175605PMC
June 2021

Analysis of 612 Benign Papillomas Diagnosed At Core Biopsy: Rate of Upgrade to Malignancy, Factors Associated with Upgrade, and A Proposal For Selective Surgical Excision.

AJR Am J Roentgenol 2021 May 19. Epub 2021 May 19.

Benjamin Felson Endowed Chair & Professor of Radiology, Department of Radiology, University of Cincinnati College of Medicine, 234 Goodman Street, ML 0761, Cincinnati, OH 45267-0761.

Despite numerous published studies, management of benign papillomas without atypia remains controversial. To determine the malignancy upgrade rate of benign papillomas, identify risk factors for upgrade, and formulate criteria for selective surgery. This retrospective study included benign papillomas without atypia diagnosed on percutaneous biopsy between 12/01/2000 and 12/31/2019. Papillomas that did not undergo surgical excision or at least 2 years of imaging and/or clinical follow-up were excluded. Clinical, imaging, and histopathologic features were extracted from the electronic medical record. Features associated with upgrade to malignancy were identified. Multivariable logistic regression was performed. The study included 612 benign papillomas in 543 women (mean age 54.5 ± 12.1 years); 466 papillomas were excised, and 146 underwent imaging/clinical surveillance. The upgrade rate to malignancy was 2.3% (14/612). Upgrade rate was associated (p<.05) with radiology-pathology correlation (50.0% if discordant vs 2.1% if concordant), patient age (5.6% for age ≥60 vs 0.7% for age <60), presenting symptoms (6.7% if palpable mass or pathologic nipple discharge vs 1.3% if no symptoms), and lesion size (7.3% if ≥10 mm vs 0.6% if <10 mm). Three of 14 upgraded papillomas were associated with ≥4 metachronous or concurrent peripheral papillomas. No incidental papilloma or papilloma reported as completely excised on core biopsy histopathologic analysis was upgraded. A predictive model combining radiology-pathology discordance, symptoms (palpable mass or nipple discharge), age ≥60, size ≥10 mm, and presence of ≥4 metachronous or concurrent peripheral papillomas achieved AUC 0.91, sensitivity 79%, and specificity 89% for upgrade. Selective surgery based on presence of any of these five factors, while excluding from surgery incidental papillomas and papillomas reported as completely excised on histopathology, would spare 294 of 612 lesions from routine excision, while identifying all 14 upgraded lesions. Benign non-atypical papillomas have a low malignancy upgrade rate; routine surgical excision may not be necessary. Selective excision is recommended for lesions satisfying any of the 5 criteria. Incidental papillomas or papillomas completely excised on histopathology may undergo imaging follow-up. The proposed criteria for selective surgery of benign papillomas on core biopsy would reduce surgeries without delaying diagnosis of malignancy.
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http://dx.doi.org/10.2214/AJR.21.25832DOI Listing
May 2021

Characterization of common breast MRI abnormalities: comparison between abbreviated and full MRI protocols.

Clin Imaging 2021 Nov 29;79:125-132. Epub 2021 Apr 29.

Department of Radiology, University of Cincinnati Medical Center, 234 Goodman Street ML 0772, Cincinnati, OH 45219-0772, United States of America. Electronic address:

Rationale And Objectives: To evaluate the diagnostic performance of abbreviated MRI (AB-MRI) in comparison to a full protocol MRI (FP-MRI) when evaluating common MRI abnormalities of a mass, non-mass enhancement and focus.

Materials And Methods: This retrospective reader study was Institutional Review Board approved and Health Insurance Portability and Accountability Act (HIPAA) compliant. AB-MRIs were reviewed from May 2018-December 2019 to identify women with an abnormal AB-MRI, FP-MRI within six months of the AB-MRI and an elevated risk for breast cancer. Six breast radiologists initially interpreted and recorded findings from the AB-MRI. Immediately after reviewing the AB-MRI, the same radiologists interpreted and recorded findings from the FP-MRI. Findings were recorded in an electronic data collection form. Cohen's Kappa test was used to calculate agreement. P < 0.05 was considered statistically significant.

Results: Of 119 patients who had an AB-MRI, our final study comprised of 32 patients who had 64 breast MRIs (32 AB-MRI and 32 FP-MRI). The amount of fibroglandular tissue for AB-MRI and FP-MRI showed excellent intra-reader agreement [Kappa: 0.89-1.00 (P < 0.0001)]. Substantial to excellent intra-reader agreement [Kappa: 0.74-0.93 (P < 0.0001)] was demonstrated for all 6 readers when identifying abnormalities seen on AB-MRI and FP-MRI. Moderate to excellent intra-reader agreement [Kappa: 0.41-0.87(P < 0.0001)] was demonstrated between the AB-MRI and FP-MRI for the final BI-RADS assessment.

Conclusion: AB-MRI has acceptable intra-reader agreement with FP-MRI when characterizing common MRI abnormalities such as a mass, non-mass enhancement and focus suggesting that subsequent FP-MRI may not be needed.
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http://dx.doi.org/10.1016/j.clinimag.2021.04.013DOI Listing
November 2021

Fetal liver hematopoiesis: from development to delivery.

Stem Cell Res Ther 2021 02 17;12(1):139. Epub 2021 Feb 17.

Center for Stem Cell & Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Clinical transplants of hematopoietic stem cells (HSC) can provide a lifesaving therapy for many hematological diseases; however, therapeutic applications are hampered by donor availability. In vivo, HSC exist in a specified microenvironment called the niche. While most studies of the niche focus on those residing in the bone marrow (BM), a better understanding of the fetal liver niche during development is vital to design human pluripotent stem cell (PSC) culture and may provide valuable insights with regard to expanding HSCs ex vivo for transplantation. This review will discuss the importance of the fetal liver niche in HSC expansion, a feat that occurs during development and has great clinical potential. We will also discuss emerging approaches to generate expandable HSC in cell culture that attain more complexity in the form of cells or organoid models in combination with engineering and systems biology approaches. Overall, delivering HSC by charting developmental principles will help in the understanding of the molecular and biological interactions between HSCs and fetal liver cells for their controlled maturation and expansion.
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http://dx.doi.org/10.1186/s13287-021-02189-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890853PMC
February 2021

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.

Gastroenterology 2021 02 8;160(3):831-846.e10. Epub 2020 Oct 8.

Division of Gastroenterology, Hepatology & Nutrition, Developmental Biology and Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Communication Design Center, Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Japan. Electronic address:

Background & Aims: Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution.

Methods: We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform.

Results: HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis.

Conclusions: Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.
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http://dx.doi.org/10.1053/j.gastro.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878295PMC
February 2021

Erythroid Lineage Cells in the Liver: Novel Immune Regulators and Beyond.

Authors:
Li Yang Kyle Lewis

J Clin Transl Hepatol 2020 Jun 8;8(2):177-183. Epub 2020 Jun 8.

Division of Gastroenterology, Hepatology & Nutrition Developmental Biology Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

The lineage of the erythroid cell has been revisited in recent years. Instead of being classified as simply inert oxygen carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential developmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In this review, we explain the natural history of erythroid cells in the liver through a developmental lens, as it offers perspectives into newly recognized roles of this lineage in liver biology. Here, we review the known immune roles of erythroid cells and discuss the mechanisms in the context of disease models and stages. Then, we explore the capability of erythroid lineage as a cell source for regenerative medicine. We propose that the versatile lineage of erythroid cells provides an underappreciated and potentially promising area for basic and translational research in the field of liver disease.
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http://dx.doi.org/10.14218/JCTH.2019.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438359PMC
June 2020

p66ShcA functions as a contextual promoter of breast cancer metastasis.

Breast Cancer Res 2020 01 15;22(1). Epub 2020 Jan 15.

Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.

Background: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis.

Methods: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo.

Results: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site.

Conclusion: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.
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http://dx.doi.org/10.1186/s13058-020-1245-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964019PMC
January 2020

Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids.

Cell Metab 2019 08 30;30(2):374-384.e6. Epub 2019 May 30.

Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan; Institute of Research, Division of Advanced Research, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Electronic address:

Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments.
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http://dx.doi.org/10.1016/j.cmet.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687537PMC
August 2019

Massive Orbital Extension of a Congenital Dacryocystocele in a 9 Month Old.

Ophthalmic Plast Reconstr Surg 2019 Jan/Feb;35(1):e25

Department of Ophthalmology, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A.

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http://dx.doi.org/10.1097/IOP.0000000000001175DOI Listing
December 2019

Gankyrin Promotes Tumor-Suppressor Protein Degradation to Drive Hepatocyte Proliferation.

Cell Mol Gastroenterol Hepatol 2018 24;6(3):239-255. Epub 2018 May 24.

Department of Surgery, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background & Aims: Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation.

Methods: We generated Gank liver-specific knock-out (GLKO) mice and examined liver biology and proliferation after surgical resection and liver injury.

Results: Global profiling of gene expression in GLKO mice showed significant changes in pathways involved in liver cancer and proliferation. Investigations of liver proliferation after partial hepatectomy and CCl treatment showed that GLKO mice have dramatically inhibited proliferation of hepatocytes at early stages after surgery and injury. In control LoxP mice, liver proliferation was characterized by Gank-mediated reduction of tumor-suppressor proteins (TSPs). The failure of GLKO hepatocytes to proliferate is associated with a lack of down-regulation of these proteins. Surprisingly, we found that hepatic progenitor cells of GLKO mice start proliferation at later stages and restore the original size of the liver at 14 days after partial hepatectomy. To examine the proliferative activities of Gank in cancer cells, we used a small molecule, cjoc42, to inhibit interactions of Gank with the 26S proteasome. These studies showed that Gank triggers degradation of TSPs and that cjoc42-mediated inhibition of Gank increases levels of TSPs and inhibits proliferation of cancer cells.

Conclusions: These studies show that Gank promotes hepatocyte proliferation by elimination of TSPs. This work provides background for the development of Gank-mediated therapy for the treatment of liver cancer. RNA sequencing data can be accessed in the NCBI Gene Expression Omnibus: GSE104395.
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http://dx.doi.org/10.1016/j.jcmgh.2018.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083020PMC
July 2019

Transactive memory systems in context: A meta-analytic examination of contextual factors in transactive memory systems development and team performance.

J Appl Psychol 2019 Mar 19;104(3):464-493. Epub 2018 Jul 19.

Moore School of Business.

Research on transactive memory systems (TMS) has been conducted in a variety of teams, a range of task types and increasingly, in settings around the world. Despite this proliferation, there has been relative inattention to contextual factors that produce TMS and explain heterogeneity in the TMS to team performance relationship. TMS studies are typically conducted in homogeneous settings (i.e., teams located in a single country) and often with sources of potential variation (i.e., environmental volatility, leadership, team human capital, and diversity) in TMS development controlled. Collating these individual studies, we use meta-analytic techniques to illuminate key contextual factors that may shape TMS and influence the TMS-performance association. Using 76 empirical studies representing 6,869 sampling units, we find that the strength of the TMS to performance relationship varies, depending on features of the national cultural context-the impact of TMS is stronger in cultural contexts where power distance and in-group collectivism are higher. Our results also suggest that environmental volatility, leadership effectiveness, and team human capital are positively associated with TMS, and informational and gender diversity are negatively associated with TMS development. Our findings also indicate fruitful areas for future research specifically aimed toward disentangling the effects of environmental, team, and national cultural context on TMS and team performance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/apl0000329DOI Listing
March 2019

The robust, readily available cobalt(iii) trication [Co(NHCHPhCHPhNH)] is a progenitor of broadly applicable chirality and prochirality sensing agents.

Chem Sci 2018 Jun 11;9(22):5087-5099. Epub 2018 May 11.

Department of Chemistry , Texas A&M University , P.O. Box 30012 , College Station , Texas 77842-3012 , USA . Email:

When NMR spectra of chiral racemic organic molecules containing a Lewis basic functional group are recorded in the presence of air and water stable salts of the cobalt(iii) trication [Co((,)-NHCHPhCHPhNH)] (), separate signals are usually observed for the enantiomers (28 diverse examples, >12 functional groups). Several chiral molecules can be simultaneously analyzed, and enantiotopic groups in prochiral molecules differentiated (16 examples). Particularly effective are the mixed bis(halide)/tetraarylborate salts Λ- 2XBAr (X = Cl, I; BAr = B(3,5-CH(CF))), which are applied in CDCl or CDCl at 1-100 mol% (avg 34 and 14 mol%). Job plots establish 1 : 1 binding for Λ- 2ClBAr and 1-phenylethyl acetate () or 1-phenylethanol (), and 1 : 2 binding with DMSO (CDCl). Selected binding constants are determined, which range from 7.60-2.73 M for the enantiomers of to 28.1-22.6 M for the enantiomers of . The NH moieties of the faces of the trication are believed to hydrogen bond to the Lewis basic functional groups, as seen in the crystal structure of a hexakis(DMSO) solvate of Λ- 3I. These salts rank with the most broadly applicable chirality sensing agents discovered to date.
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http://dx.doi.org/10.1039/c8sc01510dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994889PMC
June 2018

Changes in peripapillary blood vessel density in Graves' orbitopathy after orbital decompression surgery as measured by optical coherence tomography angiography.

Orbit 2019 Apr 8;38(2):87-94. Epub 2018 Mar 8.

b Department of Preventive Medicine , University of Mississippi Medical Center , Jackson , MS , USA.

The purpose is to evaluate the utility of optical coherence tomography (OCT) angiography in the evaluation of Graves' orbitopathy (GO) and response to orbital decompression in patients with and without dysthyroid optic neuropathy (DON). This was a single-center, prospective case series in a cohort of 12 patients (24 orbits) with GO and ±DON, (6 orbits) who underwent bilateral orbital decompression. All patients underwent pre- and postoperative OCT angiography of the peripapillary area. Vessel density indices were calculated in a 4.5 mm × 4.5 mm ellipsoid centered on the optic disk using split-spectrum amplitude decorrelation angiography algorithm, producing the vessel density measurements. Mean change in vessel density indices was compared between pre- and postoperative sessions and between patients with and without DON. Patient 1, a 34-year-old male with GO and unilateral DON OD, showed a significant reduction in blood vessel density indices oculus dexter (OD) (DON eye) after decompression while a more modest reduction was found oculus sinister (OS) with the greatest change noted intrapapillary. Patient 2, a 50-year-old male with DON OU, showed worsening neuropathy following decompression OD that was confirmed by angiographic density indices. Patient 3, a 55-year-female with DON, showed a reduction in blood vessel density OD and increased density OS. Patients without DON showed overall less impressive changes in indices as compared to those with DON. Using OCT angiography, response to surgical treatment in GO orbits, more so in orbits with DON, can be demonstrated and quantified using vessel density indices with reproducibility.
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http://dx.doi.org/10.1080/01676830.2018.1446539DOI Listing
April 2019

Tumoroid à la carte: Path for personalization.

Hepatology 2018 09 14;68(3):1189-1191. Epub 2018 May 14.

Division of Gastroenterology, Hepatology & Nutrition Developmental Biology Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

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http://dx.doi.org/10.1002/hep.29846DOI Listing
September 2018

Complete inferior rectus muscle transection secondary to orbital blowout fracture.

Orbit 2018 Dec 5;37(6):444-446. Epub 2018 Jan 5.

a Department of Ophthalmology , University of Mississippi Medical Center , Jackson , Mississippi , USA.

Complete extraocular muscle transection is uncommon in the setting of blunt trauma. We report a case of a 53-year-old male that developed diplopia after hitting his face directly on a concrete slab after a fall. On examination, he had a right hypertropia with a complete infraduction deficit. A CT scan of the face showed an orbital floor blowout fracture with complete inferior rectus transection. On surgical exploration, the distal and proximal ends of the muscle were identified and sutured together, and the floor fracture was repaired. At his post-operative visits, the patient had a persistent infraduction deficit, but subjectively had improved diplopia.
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http://dx.doi.org/10.1080/01676830.2017.1423360DOI Listing
December 2018

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner.

Mol Cell Biol 2017 Aug 28;37(16). Epub 2017 Jul 28.

Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1. Searching for mechanisms of this elimination, we found that the oncoprotein gankyrin (Gank) preferentially binds to and triggers degradation of dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) or S302A mutant CUGBP1. To test the role of Gank in degradation of CUGBP1, we generated mice with liver-specific deletion of Gank. In these mice, the tumor suppressor isoform of CUGBP1 is protected from Gank-mediated degradation. Consistent with reduction of CUGBP1 in animal models, CUGBP1 is reduced in patients with pediatric liver cancer. Thus, this work presents evidence that de-ph-S302-CUGBP1 is a tumor suppressor protein and that the Gank-UPS-mediated reduction of CUGBP1 is a key event in the development of liver cancer.
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http://dx.doi.org/10.1128/MCB.00128-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533886PMC
August 2017

FXR-Gankyrin axis is involved in development of pediatric liver cancer.

Carcinogenesis 2017 07;38(7):738-747

Departments of Surgery.

The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.
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http://dx.doi.org/10.1093/carcin/bgx050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862323PMC
July 2017

Syntheses of Families of Enantiopure and Diastereopure Cobalt Catalysts Derived from Trications of the Formula [Co(NHCHArCHArNH)].

Inorg Chem 2017 Feb 8;56(4):2304-2320. Epub 2017 Feb 8.

Department of Chemistry, Texas A&M University , P.O. Box 30012, College Station, Texas 77842-3012, United States.

Aerobic reactions of CoX (X = OAc, Cl) or Co(ClO) with (S,S)-1,2-diphenylethylenediamine [(S,S)-dpen] in CHOH, followed by HCl or HClO additions, give the diastereomeric lipophobic salts Λ-[Co((S,S)-dpen)]3Cl [Λ-(S,S)-13Cl] or Δ-(S,S)-13ClO (60-65%) with high degrees of selectivity. Anion metatheses (room temperature) and equilibrations (charcoal, CHOH, 70 °C) show that the former is more stable than Δ-(S,S)-13Cl, and the latter is more stable than Λ-(S,S)-13ClO. Additional anion metatheses lead to large families of lipophilic salts Λ- and Δ-(S,S)-12XX' [X/X' = Cl/BAr [BAr = B(3,5-CH(CF))], PF/BAr, BF/BAr, PhBF/BAr, Cl/BAr [BAr = B(CF)], BAr/BAr, BAr/BAr, BF/BF, PF/PF]. Mixed salts of the formula Λ- and Δ-[Co((S,S)-NHCHArCHArNH)]2ClBAr are similarly prepared (Ar = 4-CHn-Bu, 4-CHCl, 4-CHCF, 4-CHOCH, α-naphthyl, β-naphthyl, 2-CHOBn). The diastereotopic NHH' protons exhibit different H NMR signals; one shifts far downfield when X/X' = Cl/BAr (δ ca. 8.0 vs 4.0 ppm). This is believed to arise from hydrogen bonding between the two Cl anions and the two C faces of the D-symmetric trication, each of which feature three synperiplanar NH groups. When all of the anions are poor hydrogen-bond acceptors (e.g., BAr, BF, ClO), equilibria favor Δ diastereomers.
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http://dx.doi.org/10.1021/acs.inorgchem.6b03042DOI Listing
February 2017

Octahedral Werner complexes with substituted ethylenediamine ligands: a stereochemical primer for a historic series of compounds now emerging as a modern family of catalysts.

Chem Soc Rev 2016 Dec 20;45(24):6799-6811. Epub 2016 Oct 20.

Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, USA.

As reported by Alfred Werner in 1911-1912, salts of the formally D symmetric [Co(en)] (en = ethylenediamine) trication were among the first chiral inorganic compounds to be resolved into enantiomers, the absolute configurations of which are denoted Λ (left handed helix) or Δ (right handed helix). After a >100 year dormant period during which few useful reactions of these substitution inert complexes were described, carbon substituted derivatives have recently been found to be potent catalysts for enantioselective organic synthesis. This review systematically outlines the fascinating range of stereoisomers that can arise, such as conformers associated with the five membered chelate rings (λ/δ), alignment modes of the C-C bonds with the C symmetry axis (lel/ob), geometric isomers (fac/mer), and configurational diastereomers (R/S) arising from carbon stereocenters. These analyses demonstrate a profound stereochemical diversity that can be applied in catalyst optimization. Efforts are made to bridge the often orthogonal nomenclature systems inorganic and organic chemists employ to describe these phenomena.
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http://dx.doi.org/10.1039/c6cs00604cDOI Listing
December 2016

Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease.

Cell Rep 2016 07 30;16(3):744-56. Epub 2016 Jun 30.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA; Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address:

The development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD)-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD.
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http://dx.doi.org/10.1016/j.celrep.2016.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072278PMC
July 2016

Acute Abdominal Pain in the Bariatric Surgery Patient.

Emerg Med Clin North Am 2016 May 22;34(2):387-407. Epub 2016 Mar 22.

Department of Emergency Medicine, University of Texas Medical School at Houston, 6431 Fannin, 4th Floor, Houston, TX 77030, USA.

Obesity is present in epidemic proportions in the United States, and bariatric surgery has become more common. Thus, emergency physicians will undoubtedly encounter many patients who have undergone one of these procedures. Knowledge of the anatomic changes specific to these procedures aids the clinician in understanding potential complications and devising an organized differential diagnosis. This article reviews common bariatric surgery procedures, their complications, and the approach to acute abdominal pain in these patients.
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http://dx.doi.org/10.1016/j.emc.2015.12.004DOI Listing
May 2016

p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways.

Mol Cell Biol 2015 Sep 22;35(17):3005-16. Epub 2015 Jun 22.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

The histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300). While dnp300 mice did not show abnormal growth within 1 year, these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to the accumulation of heterochromatin foci in the liver of 2-month-old mice. Transcriptome sequencing (RNA-Seq) analysis showed that this inhibition of p300 also causes alterations of gene expression in many signaling pathways, including chromatin remodeling, apoptosis, DNA damage, translation, and activation of the cell cycle. Livers of dnp300 mice have a high rate of proliferation and a much higher rate of proliferation after partial hepatectomy. We found that livers of dnp300 mice are resistant to CCl4-mediated injury and have reduced apoptosis but have increased proliferation after injury. Underlying mechanisms of resistance to liver injury and increased proliferation in dnp300 mice include ubiquitin-proteasome-mediated degradation of C/EBPα and translational repression of the p53 protein by the CUGBP1-eukaryotic initiation factor 2 (eIF2) repressor complex. Our data demonstrate that p300 regulates a number of critical signaling pathways that control liver functions.
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http://dx.doi.org/10.1128/MCB.00421-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525310PMC
September 2015

Cobalt(III) Werner Complexes with 1,2-Diphenylethylenediamine Ligands: Readily Available, Inexpensive, and Modular Chiral Hydrogen Bond Donor Catalysts for Enantioselective Organic Synthesis.

ACS Cent Sci 2015 Mar 23;1(1):50-6. Epub 2015 Mar 23.

Department of Chemistry, Texas A&M University , P.O. Box 30012, College Station, Texas 77842-3012, United States.

In the quest for new catalysts that can deliver single enantiomer pharmaceuticals and agricultural chemicals, chemists have extensively mined the "chiral pool", with little in the way of inexpensive, readily available building blocks now remaining. It is found that Werner complexes based upon the D3 symmetric chiral trication [Co(en)3](3+) (en = 1,2-ethylenediamine), which features an earth abundant metal and cheap ligand type, and was among the first inorganic compounds resolved into enantiomers 103 years ago, catalyze a valuable carbon-carbon bond forming reaction, the Michael addition of malonate esters to nitroalkenes, in high enantioselectivities and without requiring inert atmosphere conditions. The title catalysts, [Co((S,S)-dpen)3](3+) ((S,S)-3 (3+)) 3X(-), employ a commercially available chiral ligand, (S,S)-1,2-diphenylethylenediamine. The rates and ee values are functions of the configuration of the cobalt center (Λ/Δ) and the counteranions, which must be lipophilic to solubilize the trication in nonaqueous media. The highest enantioselectivities are obtained with Λ and 2Cl(-)BArf (-), 2BF4 (-)BArf (-), or 3BF4 (-) salts (BArf (-) = B(3,5-C6H3(CF3)2)4 (-)). The substrates are not activated by metal coordination, but rather by second coordination sphere hydrogen bonding involving the ligating NH2 groups. Crystal structures and NMR data indicate enthalpically stronger interactions with the NH moieties related by the C3 symmetry axis, as opposed to those related by the C2 symmetry axes; rate trends and other observations suggest this to be the catalytically active site. Both Λ- and Δ-(S,S)-3 (3+) 2Cl(-)BArf (-) are effective catalysts for additions of β-ketoesters to RO2CN=NCO2R species (99-86% yields, 81-76% ee), which provide carbon-nitrogen bonds and valuable precursors to α-amino acids.
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http://dx.doi.org/10.1021/acscentsci.5b00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827665PMC
March 2015

Spontaneous Decompression Fracture in Thyroid Eye Disease.

Ophthalmic Plast Reconstr Surg 2016 Nov/Dec;32(6):e156-e157

*Department of Ophthalmology and †Ophthalmic Plastic and Reconstructive Surgery, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A.

This is a case of a 44-year-old female with a history of Graves' orbitopathy presented to the emergency department after waking from a nap with sudden onset of left facial and periorbital swelling, ecchymosis, and subconjunctival hemorrhage. A CT scan obtained in the emergency department revealed a left blowout fracture and enlarged extraocular muscles. The patient lives with her mother and both adamantly denied any trauma. The patient had sustained a spontaneous orbital fracture; a process reported but few times in the medical literature.
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http://dx.doi.org/10.1097/IOP.0000000000000354DOI Listing
February 2017

Intracranial Extension of an Orbital Epidermoid Cyst.

Ophthalmic Plast Reconstr Surg 2016 Nov/Dec;32(6):e135-e136

Department of Ophthalmology, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A.

Epidermoid and dermoid cysts represent the most common cystic lesions of the orbit and commonly arise from bony sutures or the intradiplpoic space of orbital bones. Massive intracranial extension of an epidermoid cyst arising from the intradiploic space of an orbital bone is very rarely seen. We present a case of a 55-year-old male who was incidentally found to have massive intracranial extension of an intradiploic epidermoid cyst of the superolateral orbital bone with minimal symptoms. The cyst was completely excised via a pterional craniotomy and lateral orbitotomy by neurosurgery and oculoplastic surgery teams. The patient suffered no complications and is doing very well.
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http://dx.doi.org/10.1097/IOP.0000000000000327DOI Listing
February 2017

Massive retinal gliosis in neurofibromatosis type 1.

JAMA Ophthalmol 2015 Jan;133(1):100-2

Oculoplastics Service, University of Mississippi Medical Center, Jackson.

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http://dx.doi.org/10.1001/jamaophthalmol.2014.3958DOI Listing
January 2015

A statewide assessment of smoke-free policy in multiunit housing settings.

Nicotine Tob Res 2014 Dec 23;16(12):1593-8. Epub 2014 Jul 23.

South Dakota State University, College of Nursing, Brookings, SD.

Introduction: The prevalence of smoke-free policies in multiunit housing (MUH) in South Dakota was examined. Owner beliefs about smoke-free policies were identified.

Methods: Stratified random sampling included 27 South Dakota counties classified as frontier, large rural, or urban. Data collection with MUH owners in selected counties employed a telephone survey with mailed backup.

Results: The owner response rate was 41.5% (324/780). A written smoke-free policy was reported by 175 (54.0%) owners, and 31 (10%) reported a verbal smoke-free policy. Owners in large rural counties (57.4%) had more written smoke-free policies than owners in urban (52.2%) and frontier (53.5%) counties. Only 8.5% of properties had policies covering both buildings and grounds. Owners without policies were more than twice as likely to manage U.S. Department of Housing and Urban Development subsidized units and were three times as likely to be current smokers. Owners without a smoke-free policy anticipated that a policy would decrease maintenance costs but increase turnover and vacancy rates. Nearly one-half (47.9%) of owners with no smoke-free policy had previously considered implementing a policy. Owners self-reported beliefs about smoke-free policies identified perceived benefits such as decreased maintenance and costs, improved tenant safety and health, and conscientious tenants. Perceived drawbacks included increased outdoor maintenance, enforcement problems, concerns about long-term tenants who smoke, and freedom/rights of smokers.

Conclusions: This study provides a baseline assessment of smoke-free polices in MUH settings. Perceptions of owners without smoke-free policies focused on economic concerns that were inconsistent with reports from those owners with smoke-free policies.
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http://dx.doi.org/10.1093/ntr/ntu114DOI Listing
December 2014

Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration.

Hepatology 2015 Jan 20;61(1):315-25. Epub 2014 Nov 20.

Huffington Center on Aging and Departments of Pathology and Immunology and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.

Unlabelled: Liver cancer is the fifth most common cancer. A highly invasive surgical resection of the liver tumor is the main approach used to eliminate the tumor. Mechanisms that terminate liver regeneration when the liver reaches the original size are not known. The aims of this work were to generate an animal model that fails to stop liver regeneration after surgical resections and elucidate mechanisms that are involved in termination of liver regeneration. Because epigenetic control of liver function has been previously implicated in the regulation of liver proliferation, we generated C/EBPα-S193A knockin mice, which have alterations in formation of complexes of C/EBP family proteins with chromatin remodeling proteins. The C/EBPα-S193A mice have altered liver morphology and altered liver function leading to changes of glucose metabolism and blood parameters. Examination of the proliferative capacity of C/EBPα-S193A livers showed that livers of S193A mice have a higher rate of proliferation after birth, but stop proliferation at the age of 2 months. These animals have increased liver proliferation in response to liver surgery as well as carbon tetrachloride (CCl4 )-mediated injury. Importantly, livers of C/EBPα-S193A mice fail to stop liver regeneration after surgery when livers reach the original, preresection, size. The failure of S193A livers to stop regeneration correlates with the epigenetic repression of key regulators of liver proliferation C/EBPα, p53, FXR, SIRT1, PGC1α, and TERT by C/EBPβ-HDAC1 complexes. The C/EBPβ-HDAC1 complexes also repress promoters of enzymes of glucose synthesis PEPCK and G6Pase.

Conclusion: Proper cooperation of C/EBP and chromatin remodeling proteins is essential for the termination of liver regeneration after surgery and for maintenance of liver functions.
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http://dx.doi.org/10.1002/hep.27295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280321PMC
January 2015

Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments.

J Biol Chem 2014 Jan 22;289(2):1106-18. Epub 2013 Nov 22.

From the Huffington Center on Aging and.

The aged liver is more sensitive to the drug treatments and has a high probability of developing liver disorders such as fibrosis, cirrhosis, and cancer. Here we present mechanisms underlying age-associated severe liver injury and acceleration of liver proliferation after CCl4 treatments. We have examined liver response to CCl4 treatments using old WT mice and young C/EBPα-S193D knockin mice, which express an aged-like isoform of C/EBPα. Both animal models have altered chromatin structure as well as increased liver injury and proliferation after acute CCl4 treatments. We found that these age-related changes are associated with the repression of key regulators of liver biology: C/EBPα, Farnesoid X Receptor (FXR) and telomere reverse transcriptase (TERT). In quiescent livers of old WT and young S193D mice, the inhibition of TERT is mediated by HDAC1-C/EBPα complexes. After CCl4 treatments, TERT, C/EBPα and FXR are repressed by different mechanisms. These mechanisms include the increase of a dominant negative isoform, C/EBPβ-LIP, and subsequent repression of C/EBPα, FXR, and TERT promoters. C/EBPβ-LIP also disrupts Rb-E2F1 complexes in C/EBPα-S193D mice after CCl4 treatments. To examine if these alterations are involved in drug-mediated liver diseases, we performed chronic treatments of mice with CCl4. We found that C/EBPα-S193D mice developed fibrosis much more rapidly than WT mice. Thus, our data show that the age-associated alterations of C/EBP proteins create favorable conditions for the increased liver proliferation after CCl4 treatments and for development of drug-mediated liver diseases.
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http://dx.doi.org/10.1074/jbc.M113.526780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887178PMC
January 2014
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