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Publication Record


Inactivation of in Abcg2 lineage-derived cells drives the appearance of polycystic lesions and fibrosis in the adult kidney.
Gewin LS, Summers ME, Harral JW, Gaskill CF, Khodo SN, Neelisetty S, Sullivan TM, Hopp K, Reese JJ, Klemm DJ, Kon V, Ess KC, Shi W, Majka SM
(2019) Am J Physiol Renal Physiol 317: F1201-F1210
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Cell Lineage, Female, Fibrosis, Kidney Tubules, Proximal, Male, Mice, Myofibroblasts, Polycystic Kidney Diseases, Selective Estrogen Receptor Modulators, Tamoxifen, Tuberous Sclerosis Complex 2 Protein
Show Abstract · Added March 18, 2020
Tuberous sclerosis complex 2 (TSC2), or tuberin, is a pivotal regulator of the mechanistic target of rapamycin signaling pathway that controls cell survival, proliferation, growth, and migration. Loss of function manifests in organ-specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of the kidney has identified ATP-binding cassette G2 (Abcg2) expression in renal proximal tubules of adult mice as well as a in a novel cell population. The impact in adult kidney of knockdown in the Abcg2-expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated , lacking exons 36-37 with an intact 3' region and polycystin 1, is driven by Here, we demonstrate that selective expression of in the Abcg2 lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells, which results in progressive proximal tubule injury, impaired kidney function, formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of function in the Abcg2-expressing proximal tubule epithelium and mesenchyme during the development of cystic lesions and remodeling of kidney parenchyma.
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13 MeSH Terms
Loss of MYO5B Leads to Reductions in Na Absorption With Maintenance of CFTR-Dependent Cl Secretion in Enterocytes.
Engevik AC, Kaji I, Engevik MA, Meyer AR, Weis VG, Goldstein A, Hess MW, Müller T, Koepsell H, Dudeja PK, Tyska M, Huber LA, Shub MD, Ameen N, Goldenring JR
(2018) Gastroenterology 155: 1883-1897.e10
MeSH Terms: Animals, Aquaporins, Chlorides, Cystic Fibrosis Transmembrane Conductance Regulator, Duodenum, Enterocytes, Gene Silencing, Humans, Intestinal Mucosa, Intestines, Malabsorption Syndromes, Mice, Mice, Knockout, Microvilli, Mucolipidoses, Myosin Type V, Protein Transport, Sodium-Glucose Transporter 1, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers, Sucrase-Isomaltase Complex, Tamoxifen
Show Abstract · Added February 7, 2019
BACKGROUND & AIMS - Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), but the physiological cause of the diarrhea associated with this disease is unclear. We investigated whether loss of MYO5B results in aberrant expression of apical enterocyte transporters.
METHODS - We studied alterations in apical membrane transporters in MYO5B-knockout mice, as well as mice with tamoxifen-inducible, intestine-specific disruption of Myo5b (VilCre;Myo5b mice) or those not given tamoxifen (controls). Intestinal tissues were collected from mice and analyzed by immunostaining, immunoelectron microscopy, or cultured enteroids were derived. Functions of brush border transporters in intestinal mucosa were measured in Ussing chambers. We obtained duodenal biopsy specimens from individuals with MVID and individuals without MVID (controls) and compared transporter distribution by immunocytochemistry.
RESULTS - Compared to intestinal tissues from littermate controls, intestinal tissues from MYO5B-knockout mice had decreased apical localization of SLC9A3 (also called NHE3), SLC5A1 (also called SGLT1), aquaporin (AQP) 7, and sucrase isomaltase, and subapical localization of intestinal alkaline phosphatase and CDC42. However, CFTR was present on apical membranes of enterocytes from MYO5B knockout and control mice. Intestinal biopsies from patients with MVID had subapical localization of NHE3, SGLT1, and AQP7, but maintained apical CFTR. After tamoxifen administration, VilCre;Myo5b mice lost apical NHE3, SGLT1, DRA, and AQP7, similar to germline MYO5B knockout mice. Intestinal tissues from VilCre;Myo5b mice had increased CFTR in crypts and CFTR localized to the apical membranes of enterocytes. Intestinal mucosa from VilCre;Myo5b mice given tamoxifen did not have an intestinal barrier defect, based on Ussing chamber analysis, but did have decreased SGLT1 activity and increased CFTR activity.
CONCLUSIONS - Although trafficking of many apical transporters is regulated by MYO5B, trafficking of CFTR is largely independent of MYO5B. Decreased apical localization of NHE3, SGLT1, DRA, and AQP7 might be responsible for dysfunctional water absorption in enterocytes of patients with MVID. Maintenance of apical CFTR might exacerbate water loss by active secretion of chloride into the intestinal lumen.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.
Grouthier V, Lebrun-Vignes B, Glazer AM, Touraine P, Funck-Brentano C, Pariente A, Courtillot C, Bachelot A, Roden DM, Moslehi JJ, Salem JE
(2018) Heart 104: 1859-1863
MeSH Terms: Action Potentials, Adolescent, Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aromatase Inhibitors, Cardiotoxicity, Databases, Factual, Europe, Female, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, Middle Aged, Prognosis, Risk Assessment, Risk Factors, Selective Estrogen Receptor Modulators, Tamoxifen, Torsades de Pointes, Young Adult
Show Abstract · Added October 1, 2018
OBJECTIVE - A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.
METHODS - We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.
RESULTS - SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.
CONCLUSIONS - SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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23 MeSH Terms
Autochthonous tumors driven by loss have an ongoing requirement for the RBP2 histone demethylase.
McBrayer SK, Olenchock BA, DiNatale GJ, Shi DD, Khanal J, Jennings RB, Novak JS, Oser MG, Robbins AK, Modiste R, Bonal D, Moslehi J, Bronson RT, Neuberg D, Nguyen QD, Signoretti S, Losman JA, Kaelin WG
(2018) Proc Natl Acad Sci U S A 115: E3741-E3748
MeSH Terms: Alleles, Animals, DNA-Binding Proteins, Echocardiography, Enzyme Activation, Fibroblasts, Genes, Retinoblastoma, Heart Septal Defects, Histone Code, Integrases, Jumonji Domain-Containing Histone Demethylases, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Neoplasm Proteins, Pituitary Neoplasms, Recombinant Fusion Proteins, Retinoblastoma Protein, Tamoxifen, Thyroid Neoplasms, Transgenes
Show Abstract · Added April 22, 2018
Inactivation of the retinoblastoma gene () product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline deletion significantly impedes tumorigenesis in mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.
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21 MeSH Terms
Gcg knockin mice as a tool for genetic manipulation in pancreatic alpha cells.
Shiota C, Prasadan K, Guo P, Fusco J, Xiao X, Gittes GK
(2017) Diabetologia 60: 2399-2408
MeSH Terms: Animals, Female, Glucagon, Glucagon-Like Peptide 1, Glucagon-Secreting Cells, Immunohistochemistry, Male, Mice, Mice, Transgenic, Proglucagon, Tamoxifen
Show Abstract · Added August 13, 2019
AIMS/HYPOTHESIS - The Cre/loxP system, which enables tissue-specific manipulation of genes, is widely used in mice for diabetes research. Our aim was to develop a new Cre-driver mouse line for the specific and efficient manipulation of genes in pancreatic alpha cells.
METHODS - A Gcg knockin mouse, which expresses a tamoxifen-inducible form of Cre from the endogenous preproglucagon (Gcg) gene locus, was generated by homologous recombination. The new Gcg mouse line was crossed to the Rosa26 (R26 ) Cre reporter mouse line in order to evaluate the tissue specificity, efficiency and tamoxifen dependency of Gcg -mediated recombination. Cell types of pancreatic islets were identified using immunohistochemistry. Biochemical and physiological data, including blood glucose levels, plasma glucagon and glucagon-like peptide (GLP)-1 levels, and pancreatic glucagon content, were collected and used to assess the overall effect of Gcg gene targeting on Gcg heterozygous mice.
RESULTS - Tamoxifen-treated Gcg ;R26 mice displayed Cre reporter activity, i.e. expression of tdTomato red fluorescent protein (RFP) in all known cells that produce proglucagon-derived peptides. In the adult pancreas, RFP was detected in 94-97% of alpha cells, whereas it was detected in a negligible (~ 0.2%) proportion of beta cells. While more than 98% of cells labelled with tamoxifen-induced RFP were glucagon-positive cells, 14-25% of pancreatic polypeptide (PP)-positive cells were also positive for RFP, indicating the presence of glucagon/PP bihormonal cell population. Tamoxifen-independent expression of RFP occurred in approximately 6% of alpha cells. In contrast to alpha cells and GLP-1-producing neurons, in which RFP expression persisted for at least 5 months after tamoxifen administration (presumably due to rare neogenesis in these cell types in adulthood), nearly half of RFP-positive intestinal L cells were replaced with RFP-negative L cells over the first 2 weeks after tamoxifen administration. Heterozygous Gcg mice showed reduced Gcg mRNA levels in islets, but maintained normal levels of pancreatic and plasma glucagon. The mice did not exhibit any detectable baseline physiological abnormalities, at least in young adulthood.
CONCLUSIONS/INTERPRETATION - The newly developed Gcg knockin mouse shows faithful expression of CreER in pancreatic alpha cells, intestinal L cells and GLP-1-producing neurons. This mouse line will be particularly useful for manipulating genes in alpha cells, due to highly specific and efficient CreER-mediated recombination in this cell type in the pancreas.
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Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects.
Chen X, Austin ED, Talati M, Fessel JP, Farber-Eger EH, Brittain EL, Hemnes AR, Loyd JE, West J
(2017) Eur Respir J 50:
MeSH Terms: Anastrozole, Animals, Bone Morphogenetic Protein Receptors, Type II, Disease Models, Animal, Echocardiography, Estradiol, Estrogen Antagonists, Female, Fulvestrant, Hemodynamics, Humans, Hypertension, Pulmonary, Insulin Resistance, Lung, Mice, Mice, Knockout, Mutation, Nitriles, Signal Transduction, Tamoxifen, Triazoles
Show Abstract · Added March 14, 2018
Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured.Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1.Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause.
Copyright ©ERS 2017.
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21 MeSH Terms
F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.
Wang Y, Ayres KL, Goldman DA, Dickler MN, Bardia A, Mayer IA, Winer E, Fredrickson J, Arteaga CL, Baselga J, Manning HC, Mahmood U, Ulaner GA
(2017) Clin Cancer Res 23: 3053-3060
MeSH Terms: Adult, Aged, Biomarkers, Pharmacological, Breast Neoplasms, Cinnamates, Dose-Response Relationship, Drug, Estradiol, Estrogen Receptor alpha, Female, Fulvestrant, Humans, Indazoles, Middle Aged, Molecular Imaging, Molecular Targeted Therapy, Positron Emission Tomography Computed Tomography, Receptors, Estrogen, Tamoxifen
Show Abstract · Added April 6, 2017
Evaluate F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials. In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed. Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I. FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. .
©2016 American Association for Cancer Research.
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18 MeSH Terms
Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach.
Burclaff J, Osaki LH, Liu D, Goldenring JR, Mills JC
(2017) Gastroenterology 152: 762-766.e7
MeSH Terms: Animals, Apoptosis, Atrophy, Azetidines, Cell Proliferation, Cellular Reprogramming, Chief Cells, Gastric, Diphtheria Toxin, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Intrinsic Factor, Metaplasia, Mice, Parietal Cells, Gastric, Peptides, Piperazines, Plant Lectins, Stomach, Tamoxifen
Show Abstract · Added April 18, 2017
Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.
Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E
(2015) J Control Release 220: 751-7
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Biological Availability, Biotransformation, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Chemistry, Pharmaceutical, Cross-Linking Reagents, Cytochrome P-450 CYP3A, Delayed-Action Preparations, Dose-Response Relationship, Drug, Drug Carriers, Drug Stability, Female, Gastric Juice, Glucuronosyltransferase, Intestinal Secretions, Kinetics, Mice, Nanomedicine, Nanoparticles, Particle Size, Polyesters, Quercetin, Solubility, Tamoxifen
Show Abstract · Added February 15, 2016
We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.
Copyright © 2015 Elsevier B.V. All rights reserved.
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27 MeSH Terms
Estrogen-cholinergic interactions: Implications for cognitive aging.
Newhouse P, Dumas J
(2015) Horm Behav 74: 173-85
MeSH Terms: Acetylcholine, Aged, Attention, Brain, Cholinergic Agents, Cholinergic Neurons, Cognition, Cognitive Aging, Estradiol, Estrogen Replacement Therapy, Female, Humans, Learning, Memory, Short-Term, Tamoxifen
Show Abstract · Added February 22, 2016
This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects.
Published by Elsevier Inc.
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15 MeSH Terms