1,000 results on '"Joel Moss"'
Search Results
102. Ultrahigh-Resolution, Short-Length CT Detects Small Cysts That Are Associated with a Decrease in DLCO but Not FEV1 in Patients with Lymphangioleiomyomatosis
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Patricia Julien-Williams, Shirley F. Rollison, Joel Moss, A. Hasani, H. Wen, N. Quade, B. Matthew, Angelo M. Taveira-DaSilva, Tania Machado, Yun-Ching Chen, Mehdi Pirooznia, Marcus Y. Chen, Amanda M. Jones, and Mario Stylianou
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Ultrahigh resolution ,business.industry ,DLCO ,Lymphangioleiomyomatosis ,Medicine ,In patient ,Short length ,business ,Nuclear medicine ,medicine.disease - Published
- 2020
103. Pregnancy in lymphangioleiomyomatosis: clinical and lung function outcomes in two national cohorts
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Simon R. Johnson, Joel Moss, Angelo M. Taveira-DaSilva, Patricia Julien-Williams, Mario Stylianou, and J.I. Johnson
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Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Lung Neoplasms ,Vital Capacity ,Article ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,DLCO ,Pregnancy ,Forced Expiratory Volume ,Advanced disease ,Medicine ,Humans ,Lymphangioleiomyomatosis ,Adverse effect ,Lung function ,030304 developmental biology ,0303 health sciences ,business.industry ,Obstetrics ,Pregnancy Outcome ,Pneumothorax ,medicine.disease ,030228 respiratory system ,Sirolimus ,Female ,business ,Pregnancy Complications, Neoplastic ,medicine.drug - Abstract
Pregnancy in women with lymphangioleiomyomatosis (LAM) has been associated with increased complications and worsening lung function although objective data to advise patients are not available. We assessed lung function and CT scans before and after pregnancy in 16 women with LAM. During the pregnancy, pneumothorax was frequent and mean forced expiratory volume in 1 s (FEV1) fell from 77%±19% prepregnancy to 64%±25% predicted and DLCO from 66±26 to 57±26 (both p1 decline were high and 10 patients required sirolimus. Women with LAM, especially with moderate or advanced disease should be counselled regarding adverse events and loss of lung function during the pregnancy.
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- 2020
104. ARH1 in Health and Disease
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Joel Moss, Linda A. Stevens, Hiroko Ishiwata-Endo, and Jiro Kato
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0301 basic medicine ,Cancer Research ,Gs alpha subunit ,Arginine ,art1 ,Review ,Nicotinamide adenine dinucleotide ,medicine.disease_cause ,lcsh:RC254-282 ,Adenylyl cyclase ,gender bias ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,bacterial toxin ,Cyclic adenosine monophosphate ,arginine-specific mono-adp-ribosylation ,cholera toxin ,Cholera toxin ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,Cytosol ,tumorigenesis ,030104 developmental biology ,Oncology ,chemistry ,membrane repair ,030220 oncology & carcinogenesis ,loss of heterozygosity ,NAD+ kinase ,arh1 - Abstract
Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)+-dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD+ by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide. ADP-ribosylarginine hydrolase 1 (ARH1) catalyzes the cleavage of the ADP-ribose-arginine bond, regenerating (arginine)protein. Arginine-specific mono-ADP-ribosylation catalyzed by bacterial toxins was first identified as a mechanism of disease pathogenesis. Cholera toxin ADP-ribosylates and activates the α subunit of Gαs, a guanine nucleotide-binding protein that stimulates adenylyl cyclase activity, increasing cyclic adenosine monophosphate (cAMP), and resulting in fluid and electrolyte loss. Arginine-specific mono-ADP-ribosylation in mammalian cells has potential roles in membrane repair, immunity, and cancer. In mammalian tissues, ARH1 is a cytosolic protein that is ubiquitously expressed. ARH1 deficiency increased tumorigenesis in a gender-specific manner. In the myocardium, in response to cellular injury, an arginine-specific mono-ADP-ribosylation cycle, involving ART1 and ARH1, regulated the level and cellular distribution of ADP-ribosylated tripartite motif-containing protein 72 (TRIM72). Confirmed substrates of ARH1 in vivo are Gαs and TRIM72, however, more than a thousand proteins, ADP-ribosylated on arginine, have been identified by proteomic analysis. This review summarizes the current understanding of the properties of ARH1, e.g., bacterial toxin action, myocardial membrane repair following injury, and tumorigenesis.
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- 2020
105. Use of human biological materials
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
106. Preface
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Evan G. Derenzo, Eric A. Singer, and Joel Moss
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- 2020
107. Introduction to the ethics and science of clinical research
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Eric A. Singer, Joel Moss, and Evan G. DeRenzo
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Scientific enterprise ,Medical education ,Clinical research ,media_common.quotation_subject ,Disease ,Function (engineering) ,Psychology ,media_common - Abstract
Scientific research is defined as the systematic collection of information to produce generalizable findings. Clinical research is a subset of all scientific research and is defined as the systematic collection of information from humans and/or from organic material taken from humans to produce generalizable findings. The goal of clinical research is to accrue knowledge to improve the diagnosis and/or treatment of human diseases. Clinical research identifies, accumulates, organizes, and interprets information about the function of the human body in health and disease. Clinical research is vastly different from clinical medicine. Although clinical research requires knowledge and skill in the practice of clinical medicine, clinical research involves human participants in the scientific enterprise of producing new information anticipated to benefit future patients. Although some research participants may benefit directly from their enrolment in studies, individualized benefit is not always the primary goal of conducting a clinical research study.
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- 2020
108. The 'Ethics' section
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
109. Designing a clinical research study
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
110. Informed consent
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
111. Bone Marrow-Derived Mesenchymal Stromal Cells (MSCs) Modulate the Inflammatory Character of Alveolar Macrophages from Sarcoidosis Patients
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Lynn Vitale-Cross, Miklos Krepuska, Gergely Szombath, Mehrnoosh Abshari, Michael Boyajian, Ian McClain Caldwell, Krisztián Németh, Christopher T. Hogden, Joseph R. Fontana, Eva Mezey, Joel Moss, and Sandra D. MacDonald
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Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,lcsh:Medicine ,Inflammation ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,sarcoidosis ,030304 developmental biology ,0303 health sciences ,Lung ,medicine.diagnostic_test ,business.industry ,lcsh:R ,Mesenchymal stem cell ,food and beverages ,General Medicine ,alveolar macrophages ,respiratory system ,Interleukin 10 ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,Tumor necrosis factor alpha ,Bone marrow ,medicine.symptom ,cell therapy ,business ,bone marrow stromal cells - Abstract
Sarcoidosis is a devastating inflammatory disease affecting many organs, especially the lungs and lymph nodes. Bone marrow-derived mesenchymal stromal cells (MSCs) can &ldquo, reprogram&rdquo, various types of macrophages towards an anti-inflammatory phenotype. We wanted to determine whether alveolar macrophages from sarcoidosis subjects behave similarly by mounting an anti-inflammatory response when co-cultured with MSCs. Fifteen sarcoidosis and eight control subjects underwent bronchoscopy and bronchoalveolar lavage (BAL). Unselected BAL cells (70&ndash, 94% macrophages) were isolated and cultured with and without MSCs from healthy adults. Following stimulation of the cultured cells with lipopolysaccharide, the medium was removed to measure interleukin 10 and tumor necrosis factor alpha (IL-10 and TNF-&alpha, ). In two additional sarcoidosis subjects, flow cytometry was used to study intracellular cytokines and surface markers associated with alveolar macrophages to confirm the results. Unselected BAL cells from sarcoidosis subjects co-cultured with MSCs showed a reduction in TNF-&alpha, (pro-inflammatory M1) and an increase in IL-10 (anti-inflammatory M2) in 9 of 11 samples studied. Control subject samples showed few, if any, differences in cytokine production. Unselected BAL cells from two additional patients analyzed by flow cytometry confirmed a switch towards an anti-inflammatory state (i.e., M1 to M2) after co-culture with MSCs. These results suggest that, similarly to other macrophages, alveolar macrophages also respond to MSC contacts by changing towards an anti-inflammatory phenotype. Based on our results, we hypothesize that mesenchymal stromal cells applied to the airways might alleviate lung inflammation and decrease steroid need in patients with sarcoidosis.
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- 2020
112. Methods and procedures
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Joel Moss, Eric A. Singer, and Evan G. DeRenzo
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Computer science ,Section (archaeology) ,business.industry ,Artificial intelligence ,computer.software_genre ,business ,computer ,Natural language processing ,Sequence (medicine) - Abstract
The study procedures and methodology section describes the manipulations that will be carried out, in what sequence, and by whom. This section must be explicit and complete with specification of how measurements will be taken and how data will be analyzed; an explanation of whether participants will be randomized or blinded; and, if interventions will be performed on participants, a clarification on how they will be performed, how often, and by whom.
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- 2020
113. Risks and benefits in clinical research
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
114. Statistics, data collection and management, and record keeping
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
115. What you need to know about the regulation of clinical research
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
116. What you need to know about clinical research ethics
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
117. Recruiting research participants
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Evan G. DeRenzo, Joel Moss, and Eric A. Singer
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Medical education ,Accrual ,Informed consent ,Process (engineering) ,Psychology - Abstract
Recruiting participants is the first step in the informed consent process. Any provision of information by the investigator to a potential participant or source of participant referrals begins the informing process and shapes expectations about the clinical research project. It is important to plan this part of the study in a way that maximizes potential for participant accrual. Recruitment should employ strategies most likely to identify, engage, and enlist eligible potential participants. Recruitment strategies that produce a large fraction of inquiries from ineligible individuals suggest that the recruiting net was spread too widely. Although recruitment needs to be efficient, recruitment strategies must avoid employing coercive elements in participant accrual.
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- 2020
118. Privacy and confidentiality
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Evan G. DeRenzo, Eric A. Singer, and Joel Moss
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- 2020
119. The Lymphangioleiomyomatosis Lung Cell and Its Human Cell Models
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Sergio Harari, Olga Torre, Wendy K. Steagall, Joel Moss, Thomas N. Darling, and Gustavo Pacheco-Rodriguez
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Pulmonary and Respiratory Medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Clinical Biochemistry ,Cell ,Biology ,Loss of heterozygosity ,03 medical and health sciences ,Tuberous sclerosis ,0302 clinical medicine ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Humans ,Lymphangioleiomyomatosis ,Molecular Biology ,Skin ,Lung ,Cell Biology ,bacterial infections and mycoses ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Translational Review ,medicine.anatomical_structure ,Lymphatic system ,030228 respiratory system ,Cell culture ,030220 oncology & carcinogenesis ,Mutation ,Female ,lipids (amino acids, peptides, and proteins) - Abstract
Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle–like LAM cells, with mutations and loss of heterozygosity in the TSC1 or, more frequently, TSC2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture, and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells. A clonal population of LAM lung cells has not been established, making analysis of the cells challenging. Cell lines have been established from angiomyolipomas, a common manifestation of LAM, and from tumors from patients with TSC. Circulating LAM cells have also been isolated from blood and other body fluids. LAM cells may also be identified in clusters apparently derived from lymphatic vessels. Genetics, patterns of antigen expression, and signaling pathways have been studied in LAM lung tissue and in LAM cell models, although rarely all in the same study. We show here that LAM cells manifest differences in these characteristics, depending on the source investigated, suggesting further studies.
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- 2018
120. Optimization of a secondary VOI protocol for lung imaging in a clinical CT scanner
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Joel Moss, Han Wen, Jianhua Yao, Catherine P. Nguyen, Vissagan Gopalakrishnan, Thomas C. Larsen, and Marcus Y. Chen
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Scanner ,Tomography Scanners, X-Ray Computed ,lung texture ,nodule ,Pulmonary cyst ,87.57.n ,High resolution ,Imaging phantom ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Medical Imaging ,0302 clinical medicine ,Lung imaging ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Cyst ,Instrumentation ,CT VOI protocol ,Radiation ,Lung ,Phantoms, Imaging ,87.57.cf ,high resolution ,business.industry ,Reproducibility of Results ,87.57.qp ,medicine.disease ,pulmonary cyst ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Ct scanners ,Radiographic Image Interpretation, Computer-Assisted ,Tomography, X-Ray Computed ,business ,Nuclear medicine ,87.57.cm - Abstract
We present a solution to meet an unmet clinical need of an in‐situ “close look” at a pulmonary nodule or at the margins of a pulmonary cyst revealed by a primary (screening) chest CT while the patient is still in the scanner. We first evaluated options available on current whole‐body CT scanners for high resolution screening scans, including ROI reconstruction of the primary scan data and HRCT, but found them to have insufficient SNR in lung tissue or discontinuous slice coverage. Within the capabilities of current clinical CT systems, we opted for the solution of a secondary, volume‐of‐interest (VOI) protocol where the radiation dose is focused into a short‐beam axial scan at the z position of interest, combined with a small‐FOV reconstruction at the xy position of interest. The objective of this work was to design a VOI protocol that is optimized for targeted lung imaging in a clinical whole‐body CT system. Using a chest phantom containing a lung‐mimicking foam insert with a simulated cyst, we identified the appropriate scan mode and optimized both the scan and recon parameters. The VOI protocol yielded 3.2 times the texture amplitude‐to‐noise ratio in the lung‐mimicking foam when compared to the standard chest CT, and 8.4 times the texture difference between the lung mimicking and reference foams. It improved details of the wall of the simulated cyst and better resolution in a line‐pair insert. The Effective Dose of the secondary VOI protocol was 42% on average and up to 100% in the worst‐case scenario of VOI positioning relative to the standard chest CT. The optimized protocol will be used to obtain detailed CT textures of pulmonary lesions, which are biomarkers for the type and stage of lung diseases.
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- 2018
121. Fibrous cephalic plaques in tuberous sclerosis complex
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Joel Moss, Chyi-Chia Richard Lee, Thomas N. Darling, A.M. Treichel, Oyetewa Oyerinde, Danielle Buccine, and Claire Hong
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Skin Neoplasms ,Adolescent ,Dermatology ,Article ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Tuberous sclerosis ,0302 clinical medicine ,Tuberous Sclerosis ,Humans ,Medicine ,Hamartoma ,Child ,Retrospective Studies ,Connective tissue nevus ,integumentary system ,business.industry ,Infant ,medicine.disease ,medicine.anatomical_structure ,Scalp Dermatoses ,Child, Preschool ,Scalp ,Lymphangioleiomyomatosis ,Cohort ,Forehead ,Female ,business ,Facial Dermatoses ,030217 neurology & neurosurgery ,Cohort study - Abstract
Background Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas. Objective To describe the clinical characteristics of FCPs in TSC. Methods A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size. Results FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas. Limitations Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women. Conclusion Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC.
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- 2018
122. Mechanism of inhibition of Shiga-toxigenic Escherichia coli SubAB cytotoxicity by steroids and diacylglycerol analogues
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Hiroki Takeuchi, Masatoshi Noda, Kinnosuke Yahiro, Kohei Ogura, Joel Moss, Kimitoshi Ichimura, Sayaka Nagasawa, Takeshi Shimizu, Hiroyasu Tsutsuki, Hirotaro Iwase, Makoto Ohnishi, and Sunao Iyoda
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0301 basic medicine ,Cancer Research ,Bryostatin 1 ,Enterocyte ,030106 microbiology ,Immunology ,medicine.disease_cause ,lcsh:RC254-282 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,lcsh:QH573-671 ,Cytotoxicity ,Diacylglycerol kinase ,biology ,Chemistry ,Toxin ,lcsh:Cytology ,Shiga toxin ,Cell Biology ,AB5 toxin ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Molecular biology ,030104 developmental biology ,medicine.anatomical_structure ,Apoptosis ,biology.protein - Abstract
Shiga toxigenic Escherichia coli (STEC) are responsible for a worldwide foodborne disease, which is characterized by severe bloody diarrhea and hemolytic uremic syndrome (HUS). Subtilase cytotoxin (SubAB) is a novel AB5 toxin, which is produced by Locus for Enterocyte Effacement (LEE)-negative STEC. Cleavage of the BiP protein by SubAB induces endoplasmic reticulum (ER) stress, followed by induction of cytotoxicity in vitro or lethal severe hemorrhagic inflammation in mice. Here we found that steroids and diacylglycerol (DAG) analogues (e.g., bryostatin 1, Ingenol-3-angelate) inhibited SubAB cytotoxicity. In addition, steroid-induced Bcl-xL expression was a key step in the inhibition of SubAB cytotoxicity. Bcl-xL knockdown increased SubAB-induced apoptosis in steroid-treated HeLa cells, whereas SubAB-induced cytotoxicity was suppressed in Bcl-xL overexpressing cells. In contrast, DAG analogues suppressed SubAB activity independent of Bcl-xL expression at early time points. Addition of Shiga toxin 2 (Stx2) with SubAB to cells enhanced cytotoxicity even in the presence of steroids. In contrast, DAG analogues suppressed cytotoxicity seen in the presence of both toxins. Here, we show the mechanism by which steroids and DAG analogues protect cells against SubAB toxin produced by LEE-negative STEC.
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- 2018
123. Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase
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Jiro Kato, Mario Leutert, Joel Moss, Emilie Frugier, Roxane Feurer, Jeannette Abplanalp, Hans A. V. Kistemaker, Amedeo Caflisch, Kathrin Nowak, Dmitri V. Filippov, Michael O. Hottiger, University of Zurich, and Hottiger, Michael O
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Models, Molecular ,Proteomics ,0301 basic medicine ,Glycoside Hydrolases ,Arginine ,Science ,Poly (ADP-Ribose) Polymerase-1 ,General Physics and Astronomy ,1600 General Chemistry ,Article ,Mass Spectrometry ,General Biochemistry, Genetics and Molecular Biology ,Serine ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,ADP-Ribosylation ,1300 General Biochemistry, Genetics and Molecular Biology ,Cell Line, Tumor ,10019 Department of Biochemistry ,Animals ,Humans ,lcsh:Science ,Enzyme Assays ,chemistry.chemical_classification ,PARG ,Multidisciplinary ,030102 biochemistry & molecular biology ,Mutagenesis ,Hydrogen Peroxide ,General Chemistry ,10226 Department of Molecular Mechanisms of Disease ,3100 General Physics and Astronomy ,In vitro ,030104 developmental biology ,Enzyme ,Biochemistry ,chemistry ,ADP-ribosylation ,Mutagenesis, Site-Directed ,570 Life sciences ,biology ,lcsh:Q - Abstract
ADP-ribosylation is a posttranslational modification that exists in monomeric and polymeric forms. Whereas the writers (e.g. ARTD1/PARP1) and erasers (e.g. PARG, ARH3) of poly-ADP-ribosylation (PARylation) are relatively well described, the enzymes involved in mono-ADP-ribosylation (MARylation) have been less well investigated. While erasers for the MARylation of glutamate/aspartate and arginine have been identified, the respective enzymes with specificity for serine were missing. Here we report that, in vitro, ARH3 specifically binds and demodifies proteins and peptides that are MARylated. Molecular modeling and site-directed mutagenesis of ARH3 revealed that numerous residues are critical for both the mono- and the poly-ADP-ribosylhydrolase activity of ARH3. Notably, a mass spectrometric approach showed that ARH3-deficient mouse embryonic fibroblasts are characterized by a specific increase in serine-ADP-ribosylation in vivo under untreated conditions as well as following hydrogen peroxide stress. Together, our results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome., Nature Communications, 8 (1), ISSN:2041-1723
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- 2017
124. Addressing the challenges of lymphangioleiomyomatosis assessment in the clinic
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Joel Moss and Angelo M. Taveira-DaSilva
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Oncology ,medicine.medical_specialty ,Disease ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Everolimus ,Lung ,business.industry ,Health Policy ,bacterial infections and mycoses ,Discovery and development of mTOR inhibitors ,medicine.disease ,medicine.anatomical_structure ,Lymphatic system ,030228 respiratory system ,Sirolimus ,Lymphangioleiomyomatosis ,lipids (amino acids, peptides, and proteins) ,business ,medicine.drug - Abstract
Introduction: Lymphangioleiomyomatosis (LAM) is a disease primarily of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas.Areas covered: LAM is caused ...
- Published
- 2017
125. Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis
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Lisa M. Julian, Alexander A. Goldberg, Elizabeth P. Henske, Sean P. Delaney, Julien Yockell-Lelièvre, Joel Moss, Carole Doré, William L. Stanford, Mary-Ellen Harper, Molly S. Shoichet, Roger Y. Tam, David J. Kwiatkowski, Fiona McMurray, Arnold S. Kristof, Thomas N. Darling, Ying Wang, and Krinio Giannikou
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Somatic cell ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Induced pluripotent stem cell ,Neural crest ,bacterial infections and mycoses ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Lymphangioleiomyomatosis ,Immunology ,Cancer research ,lipids (amino acids, peptides, and proteins) ,TSC1 ,TSC2 ,Reprogramming - Abstract
Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.
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- 2017
126. Long-Term Effects of Sirolimus on Human Skin TSC2-Null Fibroblast‒Like Cells
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Gi Soo Kang, Eric M. Billings, Xiaoyan Shen, Joel Moss, Kelsey Grolig, Xiong Cai, Thomas N. Darling, Gustavo Pacheco-Rodriguez, and Qingyuan Fan
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congenital, hereditary, and neonatal diseases and abnormalities ,Skin Neoplasms ,Carcinogenesis ,Cyclin D ,Mutation, Missense ,Dermatology ,Angiofibroma ,Biochemistry ,Article ,Cell Line, Tumor ,Tuberous Sclerosis Complex 2 Protein ,Autophagy ,medicine ,Humans ,Protein kinase A ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Cell Size ,Skin ,Sirolimus ,Antibiotics, Antineoplastic ,biology ,Chemistry ,Cell growth ,TOR Serine-Threonine Kinases ,Cell Cycle ,Estrogens ,Cell Biology ,Fibroblasts ,Cell cycle ,Cellular Reprogramming ,nervous system diseases ,Ribosomal protein s6 ,Cancer research ,biology.protein ,medicine.drug - Abstract
Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by hamartomatous tumors of the skin, kidneys, brain, and lungs. TSC is caused by mutations in the TSC1 and TSC2 genes, which result in hyperactivation of the mTOR, leading to dysregulated cell growth and autophagy. Rapamycin (sirolimus) shrinks TSC tumors, but the clinical benefits of sirolimus are not sustained after its withdrawal. In this study, we studied the cellular processes critical for tumor formation and growth, including cell proliferation and cell size. TSC2(−/−) and TSC2(+/−) cells were isolated from TSC skin tumors and normal-appearing skin, respectively. Cells were incubated with sirolimus for 72 hours. Withdrawal of sirolimus from TSC2(−/−) cells resulted in a highly proliferative phenotype and caused cells to enter the S phase of the cell cycle, with persistent phosphorylation of mTOR, p70 S6 kinase, ribosomal protein S6, and 4EB-P1; decreased cyclin D kinase inhibitors; and transient hyperactivation of protein kinase B. Sirolimus modulated the estrogen- and autophagy-dependent volume of TSC2(−/−) cells. These results suggest that sirolimus may decrease the size of TSC tumors by reducing TSC2(−/−) cell volume, altering the cell cycle, and reprogramming TSC2-null cells.
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- 2021
127. Needle in the Haystack: Finding the Elusive Lymphangioleiomyomatosis Cell
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Wendy K. Steagall and Joel Moss
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Pulmonary and Respiratory Medicine ,Lung Neoplasms ,business.industry ,MEDLINE ,Original Articles ,Computational biology ,bacterial infections and mycoses ,Critical Care and Intensive Care Medicine ,medicine.disease ,Transcriptome ,immune system diseases ,Needles ,hemic and lymphatic diseases ,Lymphangioleiomyomatosis ,Humans ,Medicine ,lipids (amino acids, peptides, and proteins) ,Haystack ,Lung Diseases, Interstitial ,business - Abstract
Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. Objectives: Identification and characterization of LAM cells in human lung and uterus using a single-cell approach. Methods: Single-cell and single-nuclei RNA sequencing on LAM (n = 4) and control (n = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAM(CORE) cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM. Measurements and Main Results: A unique cell type termed LAM(CORE) was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAM(CORE) cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK, and MLANA and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAM(CORE) cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. Conclusions: A unique population of LAM(CORE) cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.
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- 2020
128. T2-weighted Lung Imaging Using a 0.55-T MRI System
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Joel Moss, Kevin P. Fennelly, Kenneth N. Olivier, Elizabeth C. Jones, Adrienne E. Campbell-Washburn, Marcus Y. Chen, and Ashkan A. Malayeri
- Subjects
business.industry ,Image quality ,Computer science ,030204 cardiovascular system & hematology ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Software ,Text mining ,Lung imaging ,Radiology, Nuclear Medicine and imaging ,Computer vision ,Artificial intelligence ,business ,T2 weighted ,Original Research - Abstract
PURPOSE: To assess a 0.55-T MRI system for imaging lung disease and to compare image quality with clinical CT scans. MATERIALS AND METHODS: In this prospective study conducted between November 2018 and December 2019, respiratory-triggered T2-weighted turbo spin-echo MRI at 0.55 T was compared with clinical CT scans in 24 participants (mean age, 59 years ± 16 [standard deviation]; 18 women) with common lung abnormalities. MR images were reviewed and scored by experienced readers. Abnormal findings identified with MRI and CT were compared using the Cohen κ statistic. RESULTS: High-quality structural pulmonary MR images were attained with an average acquisition time of 11 minutes ± 3. MRI generated sufficient image quality to robustly detect bronchiectasis (κ = 0.61), consolidative opacities (κ = 1.00), cavitary lesions (κ = 1.00), effusion (κ = 0.64), mucus plug (κ = 0.68), and solid scattered nodularity (κ = 0.82). Diffuse disease, including ground-glass opacities (κ = 0.57) and tree-in-bud nodules (κ = 0.48), were the findings that were most difficult to discern using MRI, with false readings in four of 18 patients for each feature. Nodule size, which was measured independently at CT and MRI, was strongly correlated (R(2) = 0.99) for nodules with a measurement of 10 mm ± 5 (range, 5–23 mm). CONCLUSION: This initial study indicates that high-performance 0.55-T MRI holds promise in the evaluation of common lung disease. Clinical trials registration no. NCT03331380 Supplemental material is available for this article. Keywords: MRI, Pulmonary, Technology Assessment © RSNA, 2021
- Published
- 2021
129. TRIM23 mediates virus-induced autophagy via activation of TBK1
- Author
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Chengyu Liang, Gustavo Pacheco-Rodriguez, Michaela U. Gack, Joel Moss, Martha Vaughan, Jiro Kato, Zachary M. Parker, Sebastian Gableske, Owen Pornillos, Konstantin M. J. Sparrer, Florian Full, Gavin J. Baumgart, and Matthew A. Zurenski
- Subjects
0301 basic medicine ,Microbiology (medical) ,Ubiquitin-Protein Ligases ,viruses ,Immunology ,Herpesvirus 1, Human ,GTPase ,Protein Serine-Threonine Kinases ,BAG3 ,Applied Microbiology and Biotechnology ,Microbiology ,Article ,03 medical and health sciences ,GTP-binding protein regulators ,GTP-Binding Proteins ,RNA interference ,Interferon ,Autophagy ,Genetics ,medicine ,Humans ,Encephalomyocarditis virus ,Phosphorylation ,biology ,Hydrolysis ,Ubiquitination ,Cell Biology ,Tripartite motif family ,Immunity, Innate ,3. Good health ,Ubiquitin ligase ,Cell biology ,Enzyme Activation ,030104 developmental biology ,Influenza A virus ,Host-Pathogen Interactions ,biology.protein ,RNA Interference ,Guanosine Triphosphate ,Signal Transduction ,Virus Physiological Phenomena ,medicine.drug - Abstract
Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy-mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation.
- Published
- 2017
130. An Official American Thoracic Society Workshop Report: Translational Research in Rare Respiratory Diseases
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Jennifer S. Landry, Qutayba Hamid, Lisa R. Young, Francis X. McCormack, Arnold S. Kristof, Basil J. Petrof, Frank Rauch, Maimoona A. Zariwala, Benjamin Smith, David Y. Thomas, Joel Moss, Adam J. Shapiro, Ivan O. Rosas, Alex MacKenzie, Martin Kolb, Bruce C. Trapnell, and Inga J. Murawski
- Subjects
Lung Diseases ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Consensus Development Conferences as Topic ,Alternative medicine ,Translational research ,Policy initiatives ,Translational Research, Biomedical ,Mice ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Health care ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Clinical care ,Genetic Association Studies ,Societies, Medical ,American Thoracic Society Documents ,Clinical Trials as Topic ,Medical education ,Heterogeneous group ,business.industry ,Molecular pathogenesis ,United States ,Clinical research ,030228 respiratory system ,business - Abstract
Rare respiratory diseases (RRDs) are a heterogeneous group of disorders that collectively represent a significant health care burden. In recent years, strong advocacy and policy initiatives have led to advances in the implementation of research and clinical care for rare diseases. The development of specialized centers and research networks has facilitated support for affected individuals as well as emerging programs in basic, translational, and clinical research. In selected RRDs, subsequent gains in knowledge have informed the development of targeted therapies and effective diagnostic tests, but many gaps persist. There was therefore a desire to identify the elements contributing to an effective translational research program in RRDs. To this end, a workshop was convened in October 2015 with a focus on the implementation of effective transnational research networks and collaborations aimed at developing novel diagnostic and therapeutic tools. Key elements included an emphasis on molecular pathogenesis, the continuing engagement of patient advocacy groups and policy makers, the effective use of preclinical models in the translational research pipeline, and the detailed phenotyping of patient cohorts. During the course of the workshop, current logistical and knowledge gaps were identified, and new solutions or opportunities were highlighted.
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- 2017
131. Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis
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Ivan O. Rosas, Souheil El-Chemaly, Patricia Julien-Williams, Mary Haughey, Ye Cui, Angelo M. Taveira-DaSilva, Hilary J. Goldberg, Amanda M. Jones, Rie Maurer, Don C. Bienfang, Elizabeth Peters, Joel Moss, Shefali Bagwe, Elizabeth P. Henske, and Julian A. Villalba
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Hydroxychloroquine ,Critical Care and Intensive Care Medicine ,medicine.disease ,Pulmonary function testing ,Surgery ,03 medical and health sciences ,FEV1/FVC ratio ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Sirolimus ,Internal medicine ,Lymphangioleiomyomatosis ,Mucositis ,medicine ,Cardiology and Cardiovascular Medicine ,Adverse effect ,business ,medicine.drug - Abstract
Background Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function. Methods This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks. Results Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV 1 and FVC remained stable at 48 weeks, but the 6-min walk distance showed a decrease toward baseline. Conclusions The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials. Trial Registry ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov
- Published
- 2017
132. Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway
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Kim M. Keppler-Noreuil, Leslie G. Biesecker, Thomas N. Darling, Joel Moss, and Neera R. Nathan
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,AKT1 ,Dermatology ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Skin Diseases ,Tuberous Sclerosis Complex 1 Protein ,Article ,Proteus Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Tuberous Sclerosis ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Humans ,PTEN ,Protein kinase B ,PI3K/AKT/mTOR pathway ,biology ,Mosaicism ,business.industry ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,PTEN Phosphohydrolase ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,medicine.disease ,Proteus syndrome ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Multiprotein Complexes ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,TSC1 ,Phosphatidylinositol 3-Kinase ,TSC2 ,Hamartoma Syndrome, Multiple ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mosaicism is the presence of two or more genetically distinct cell lineages originating from a single zygote. The skin frequently marks mosaic conditions through migration patterns of a population of mutant cells during embryogenesis. Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway can result in segmental overgrowth, hamartomas, and malignant tumors, given the crucial role of this axis in cell growth. Mosaicism for activating mutations in AKT1 and PIK3CA is responsible for Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. These frequently exemplify Happle’s patterns of cutaneous mosaicism. Postzygotic mutations in PTEN and TSC1/TSC2 result in mosaic forms of the PTEN Hamartoma Tumor Syndrome and tuberous sclerosis complex, which may present as disseminated or segmental disease. Distinct features observed in these mosaic conditions may be attributed to differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing methods of affected tissue is often necessary to diagnosis these disorders. Oral mTORC1 inhibitors, such as sirolimus and everolimus, are useful for treating tuberous sclerosis complex, and drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat several of these disorders.
- Published
- 2017
133. Dermatological adverse events associated with use of oral mechanistic target of rapamycin inhibitors in a cohort of individuals with tuberous sclerosis complex
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Joel Moss, Patricia Julien-Williams, Amanda M. Jones, Tania Machado, A.M. Treichel, Thomas N. Darling, and Deeti J. Pithadia
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Oncology ,medicine.medical_specialty ,Dermatology ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Article ,Cohort Studies ,Tuberous sclerosis ,Tuberous Sclerosis ,Internal medicine ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Humans ,Adverse effect ,Mechanistic target of rapamycin ,Sirolimus ,Everolimus ,biology ,business.industry ,TOR Serine-Threonine Kinases ,medicine.disease ,Cohort ,biology.protein ,business ,medicine.drug - Published
- 2020
134. A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex
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K. Burke, Thomas N. Darling, Neera R. Nathan, and Joel Moss
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Adult ,Pediatrics ,medicine.medical_specialty ,Skin Neoplasms ,Adolescent ,MEDLINE ,Dermatology ,Article ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Tuberous sclerosis ,0302 clinical medicine ,Text mining ,Tuberous Sclerosis ,Humans ,Medicine ,030212 general & internal medicine ,Young adult ,Child ,Retrospective Studies ,business.industry ,Infant, Newborn ,Infant ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Management algorithm ,Child, Preschool ,Physical therapy ,business ,Algorithms - Published
- 2016
135. A diagnostic algorithm for enhanced detection of mosaic tuberous sclerosis complex in adults
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Joel Moss, David J. Kwiatkowski, A.M. Treichel, and Thomas N. Darling
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Adult ,business.industry ,Mosaicism ,Mosaic (geodemography) ,Dermatology ,Computational biology ,medicine.disease ,DNA sequencing ,Article ,Tuberous sclerosis ,Tuberous Sclerosis ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Humans ,business ,Algorithms ,Software - Published
- 2019
136. Cholix toxin, an eukaryotic elongation factor 2 ADP‐ribosyltransferase, interacts with Prohibitins and induces apoptosis with mitochondrial dysfunction in human hepatocytes
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Kinnosuke Yahiro, Satoru Miyagi, Mamoru Satoh, Eiki Yamasaki, Mika Terasaki, Kohei Ogura, Yasuhiro Terasaki, and Joel Moss
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Programmed cell death ,Immunoprecipitation ,Poly ADP ribose polymerase ,Bacterial Toxins ,Eukaryotic Initiation Factor-2 ,Immunology ,Apoptosis ,macromolecular substances ,Mitochondrion ,Biology ,Microbiology ,Article ,03 medical and health sciences ,ADP-Ribosylation ,Tubulin ,Virology ,Prohibitins ,Humans ,Protein Isoforms ,Amino Acid Sequence ,RNA, Small Interfering ,Prohibitin ,Protein kinase A ,Vibrio cholerae ,Cell Line, Transformed ,bcl-2-Associated X Protein ,030304 developmental biology ,rho-Associated Kinases ,0303 health sciences ,Virulence ,ADP-Ribosylation Factors ,030306 microbiology ,Hep G2 Cells ,Mitochondria ,Cell biology ,Repressor Proteins ,Elongation factor ,Actin Cytoskeleton ,bcl-2 Homologous Antagonist-Killer Protein ,Gene Expression Regulation ,Host-Pathogen Interactions ,Proteolysis ,Hepatocytes ,Reactive Oxygen Species ,Protein Binding ,Signal Transduction - Abstract
Vibrio cholerae produced-Cholix toxin (Cholix) is a cytotoxin that ADP-ribosylates eukaryotic elongation factor 2, inhibiting protein synthesis, and inducing apoptosis. Here, we identified prohibitin (PHB) 1 and 2 as novel Cholix-interacting membrane proteins in immortalised human hepatocytes and HepG2 cells by Cholix immunoprecipitation assays. The expression level of PHB1 was decreased by Cholix after a 12hr incubation. Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage was significantly enhanced in PHB (PHB1 or PHB2) knockdown cells. In contrast, transiently overexpressed PHB in hepatocytes attenuated Cholix-induced Bax/Bak conformational changes and PARP cleavage. In addition, Cholix-induced reactive oxygen species production and accumulation of fragmented mitochondria were enhanced in PHB-knockdown cells. Furthermore, Cholix induced activation of Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which was enhanced in PHB-knockdown cells, followed by actin filament depolymerisation and accumulation of tubulin in the blebbing cells. Inhibition of ROCK1 by siRNA or its inhibitor suppressed Cholix-induced PARP cleavage and reactive oxygen species generation. Our findings identify PHB as a new protein that interacts with Cholix and is involved in Cholix-induced mitochondrial dysfunction and cytoskeletal rearrangement by ROCK1 activation during apoptosis.
- Published
- 2019
137. Detailed Imaging of Lung Cysts in LAM and BHD Patients by a High-Resolution Targeted CT Re-Scan
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H. Wen, Joel Moss, Marcus Y. Chen, Amanda M. Jones, Thomas C. Larsen, Patricia Julien-Williams, A. Hasani, Tania Machado, Shirley F. Rollison, and W.M. Linehan
- Subjects
business.industry ,Resolution (electron density) ,Medicine ,Nuclear medicine ,business ,Lung cysts - Published
- 2019
138. Targeted High-Resolution CT Re-Scan in Patients with Lymphangioleiomyomatosis Lead to Higher Cyst Score Accuracy
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Patricia Julien-Williams, Shirley F. Rollison, Thomas C. Larsen, A. Hasani, Joel Moss, Tania Machado, Marcus Y. Chen, Amanda M. Jones, and H. Wen
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medicine.medical_specialty ,business.industry ,Lymphangioleiomyomatosis ,medicine ,High resolution ,Cyst ,In patient ,Radiology ,Lead (electronics) ,medicine.disease ,business - Published
- 2019
139. Correlative Imaging Study of Lymphangioleiomyomatosis Tissue Sample by X-Ray Micro Tomography and Histology
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Zu-Xi Yu, Eric E. Bennett, Dumitru Mazilu, H. Wen, David T. Nguyen, Joel Moss, and Thomas C. Larsen
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Materials science ,business.industry ,Lymphangioleiomyomatosis ,X-ray ,medicine ,Tissue sample ,Histology ,Micro tomography ,Correlative imaging ,medicine.disease ,Nuclear medicine ,business - Published
- 2019
140. Circulating Lymphangioleiomyomatosis Tumor Cells With Loss of Heterozygosity in the TSC2 Gene Show Increased Aldehyde Dehydrogenase Activity
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Gustavo Pacheco-Rodriguez, Mehdi Pirooznia, Ilker Tunc, Ji-an Wang, Wendy K. Steagall, Leigh Samsel, Joel Moss, J. Philip McCoy, Pradeep K. Dagur, and Thomas N. Darling
- Subjects
Pulmonary and Respiratory Medicine ,Cell type ,Angiomyolipoma ,Aldehyde dehydrogenase ,Loss of Heterozygosity ,Critical Care and Intensive Care Medicine ,Loss of heterozygosity ,Circulating tumor cell ,immune system diseases ,hemic and lymphatic diseases ,Tuberous Sclerosis Complex 2 Protein ,Medicine ,Humans ,Lymphangioleiomyomatosis ,biology ,business.industry ,Aldehyde Dehydrogenase ,medicine.disease ,bacterial infections and mycoses ,Neoplastic Cells, Circulating ,Cancer cell ,biology.protein ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Stem cell ,Diffuse Lung Disease ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Lymphangioleiomyomatosis (LAM) is a destructive metastasizing neoplasm of the lung characterized by proliferation of LAM cells in specialized lung nodules. LAM cells are characterized by expression of the prometastatic and cancer-initiating hyaluronan receptor CD44v6, and loss of heterozygosity (LOH) of TSC1 and TSC2. The circulating neoplastic LAM cells are thought to be involved in metastasis. Because LAM cells display properties of neoplastic, metastatic, and stem cell-like cancer cells, we hypothesized that elevated aldehyde dehydrogenase (ALDH) activity, characteristic of cancer and stem cells, is a property of LAM cells. Methods We performed an in silico search of ALDH genes in microdissected LAM lung nodules. To identify circulating LAM cells, we osmotically removed red blood cells from whole blood to obtain peripheral blood mononuclear cells, which were then sorted by fluorescence-activated cell sorting based on their level of ALDH activity. Results Microdissected LAM lung nodules possess a distinctive ALDH gene profile. The cell subpopulation with high ALDH activity, isolated from circulating cells, possessed TSC2 LOH in 8 of 14 patients with LAM. Approximately 60% of the circulating cells with high ALDH activity expressed CD44v6. Cells with TSC2 LOH from patients with LAM and LAM/TSC exhibited different properties in different body locations, but all cell types showed high ALDH activity. Conclusions This new procedure allows for isolation of circulating LAM cells from cultured cells, blood, and chylous effusions and shows that circulating LAM cells are heterogeneous with neoplastic, metastatic, and cancer-stem cell-like properties.
- Published
- 2019
141. Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis
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Joel Moss, Wendy K. Steagall, Mario Stylianou, and Gustavo Pacheco-Rodriguez
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0301 basic medicine ,medicine.medical_specialty ,Angiotensin-Converting Enzyme Inhibitors ,Gastroenterology ,Pulmonary function testing ,03 medical and health sciences ,0302 clinical medicine ,DLCO ,Forced Expiratory Volume ,Internal medicine ,Diffusing capacity ,medicine ,Humans ,Lymphangioleiomyomatosis ,Lung ,Retrospective Studies ,Sirolimus ,Carbon Monoxide ,biology ,business.industry ,Standard treatment ,Angiotensin-converting enzyme ,General Medicine ,medicine.disease ,Respiratory Function Tests ,030104 developmental biology ,Enzyme inhibitor ,030220 oncology & carcinogenesis ,Disease Progression ,biology.protein ,Female ,Clinical Medicine ,business ,medicine.drug - Abstract
INTRODUCTION. A local renin-angiotensin system exists in the pulmonary nodules of lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected lymphangioleiomyomatosis disease progression. METHODS. Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. RESULTS. Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and sirolimus versus sirolimus alone. CONCLUSIONS. Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with lymphangioleiomyomatosis not treated with sirolimus. These inhibitors may be an option or adjunct in the treatment of lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. FUNDING. NIH.
- Published
- 2019
142. PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells
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Jiro Kato, Atsushi Kasamatsu, Thomas C. Markello, David H. Adams, Kazumasa Aoyama, Camilo Toro, Lynne A. Wolfe, Joel Moss, Masato Mashimo, William A. Gahl, Xiangning Bu, Hiroko Ishiwata-Endo, and Linda A. Stevens
- Subjects
Adult ,Male ,0301 basic medicine ,Poly Adenosine Diphosphate Ribose ,Programmed cell death ,Glycoside Hydrolases ,DNA damage ,Primary Cell Culture ,Poly (ADP-Ribose) Polymerase-1 ,Poly(ADP-ribose) Polymerase Inhibitors ,Gene mutation ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,PARP1 ,medicine ,Animals ,Humans ,Child ,Parthanatos ,Cells, Cultured ,Skin ,Neurons ,PARG ,Chemistry ,Neurodegeneration ,Apoptosis Inducing Factor ,Brain ,Neurodegenerative Diseases ,Hydrogen Peroxide ,General Medicine ,Fibroblasts ,Embryo, Mammalian ,medicine.disease ,Molecular biology ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Child, Preschool ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Female ,Oxidative stress ,Intracellular ,DNA Damage ,Research Article - Abstract
Poly(ADP-ribosyl)ation refers to the covalent attachment of ADP-ribose to protein, generating branched, long chains of ADP-ribose moieties, known as poly(ADP-ribose) (PAR). Poly(ADP-ribose) polymerase 1 (PARP1) is the main polymerase and acceptor of PAR in response to DNA damage. Excessive intracellular PAR accumulation due to PARP1 activation leads cell death in a pathway known as parthanatos. PAR degradation is mainly controlled by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose-acceptor hydrolase 3 (ARH3). Our previous results demonstrated that ARH3 confers protection against hydrogen peroxide (H(2)O(2)) exposure, by lowering cytosolic and nuclear PAR levels and preventing apoptosis-inducing factor (AIF) nuclear translocation. We identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. In addition, parthanatos was observed in neurons of the patient’s deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Consistent with the previous findings, the patient’s fibroblasts and ARH3-deficient mice were more sensitive, respectively, to H(2)O(2) stress and cerebral ischemia/reperfusion-induced PAR accumulation and cell death. Further, PARP1 inhibition alleviated cell death and injury resulting from oxidative stress and ischemia/reperfusion. PARP1 inhibitors may attenuate the progression of neurodegeneration in affected patients with ARH3 deficiency.
- Published
- 2019
143. A genome-wide association study implicates
- Author
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Wonji, Kim, Krinio, Giannikou, John R, Dreier, Sanghun, Lee, Magdalena E, Tyburczy, Edwin K, Silverman, Elżbieta, Radzikowska, Shulin, Wu, Chin-Lee, Wu, Elizabeth P, Henske, Gary, Hunninghake, Havi, Carel, Antonio, Roman, Miquel Angel, Pujana, Joel, Moss, Sungho, Won, and David J, Kwiatkowski
- Subjects
Aged, 80 and over ,Male ,Internationality ,Lung Neoplasms ,Base Sequence ,Genotype ,Middle Aged ,Polymorphism, Single Nucleotide ,Kidney Neoplasms ,COUP Transcription Factor II ,Logistic Models ,Case-Control Studies ,Humans ,Female ,Lymphangioleiomyomatosis ,Aged ,Genome-Wide Association Study - Abstract
Lymphangioleiomyomatosis (LAM) occurs either associated with tuberous sclerosis complex (TSC) or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown. We hypothesised that DNA sequence variants outside ofGenotyped and imputed data on 5 426 936 single nucleotide polymorphisms (SNPs) in 426 S-LAM subjects were compared, using conditional logistic regression, with similar data from 852 females from COPDGene in a matched case-control design. For replication studies, genotypes for 196 non-Hispanic White female S-LAM subjects were compared with three different sets of controls. RNA sequencing and immunohistochemistry analyses were also performed.Two noncoding genotyped SNPs met genome-wide significance: rs4544201 and rs2006950 (p=4.2×10SNPs on chromosome 15q26.2 are associated with S-LAM, and chromatin and expression data suggest that this association may occur through effects on
- Published
- 2018
144. Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair
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Hong San, Victoria Hoffmann, Zu-Xi Yu, Joel Moss, Angel Aponte, Jianfeng Zhu, Jiro Kato, Danielle A. Springer, Linda A. Stevens, Akihiko Tonouchi, Junhui Sun, Kazuyo Takeda, Youn Wook Chung, Hiroko Ishiwata-Endo, and Elizabeth Murphy
- Subjects
0301 basic medicine ,Male ,Arginine ,Ischemia ,Myocardial Reperfusion Injury ,03 medical and health sciences ,Mice ,ADP-Ribosylation ,Fibrosis ,Cell Movement ,Dobutamine ,medicine ,Myocyte ,Animals ,N-Glycosyl Hydrolases ,ADP Ribose Transferases ,Mice, Knockout ,Wound Healing ,Chemistry ,Cell Membrane ,Membrane Proteins ,General Medicine ,medicine.disease ,Cell biology ,030104 developmental biology ,ADP-ribosylation ,Myocardial fibrosis ,Female ,Wound healing ,Cardiomyopathies ,Carrier Proteins ,Reperfusion injury ,Research Article - Abstract
Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP-ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury.
- Published
- 2018
145. Methacholine reactivity in lymphangioleiomyomatosis is inversely related to FEV1 and VEGF-D
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Sergio Harari, Mario Stylianou, Gustavo Pacheco-Rodriguez, Joel Moss, Antonella Caminati, Roberto Cassandro, and Davide Elia
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung ,business.industry ,medicine.disease ,Vascular endothelial growth factor ,Tuberous sclerosis ,chemistry.chemical_compound ,medicine.anatomical_structure ,Lymphatic system ,chemistry ,Sirolimus ,Internal medicine ,Lymphangioleiomyomatosis ,medicine ,TSC1 ,Differential diagnosis ,business ,medicine.drug - Abstract
Lymphangioleiomyomatosis (LAM) is a multisystem disease characterised by cystic lung destruction, leading to respiratory failure, and associated with kidney ( e.g. , angiomyolipomas (AML)) and lymphatic involvement ( e.g. , lymphangioleiomyomas, chylous effusions) [1, 2]. LAM occurs sporadically or in association with Tuberous Sclerosis Complex (TSC), an autosomal-dominant disorder characterised by mutations of the TSC1 or TSC2 genes. Lung destruction results from the proliferation of LAM cells, which possess neoplastic properties and are found in LAM lung nodules, in association with fibroblasts, mast cells, lymphocytes and lymphatic endothelial cells [3, 4]. LAM patients may show increases in serum levels of the lymphangiogenic factor, vascular endothelial growth factor-D (VEGF-D), a LAM biomarker used in differential diagnosis of cystic lung diseases and to identify LAM patients likely to respond to sirolimus treatment [5–7]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Dr. Cassandro has nothing to disclose. Conflict of Interest: Dr. Elia has nothing to disclose. Conflict of Interest: Dr. Caminati reports personal fees from Roche, personal fees from BI, outside the submitted work. Conflict of Interest: Dr. Pacheco has nothing to disclose. Conflict of Interest: Dr. Stylianou has nothing to disclose. Conflict of Interest: Dr. Moss has nothing to disclose. Conflict of Interest: Dr. Harari has nothing to disclose.
- Published
- 2021
146. 13684 Hair graying may occur early in life in tuberous sclerosis complex and is distinct from poliosis
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Alexander M. Cartron, Alison Treichel, Deeti Pithadia, Joel Moss, and Thomas Darling
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Dermatology - Published
- 2020
147. Functional Role of ADP-Ribosyl-Acceptor Hydrolase 3 in poly(ADPRibose) Polymerase-1 Response to Oxidative Stress
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Masato Mashimo and Joel Moss
- Subjects
0301 basic medicine ,Poly Adenosine Diphosphate Ribose ,Glycoside Hydrolases ,DNA repair ,Poly ADP ribose polymerase ,Poly (ADP-Ribose) Polymerase-1 ,Plasma protein binding ,Biochemistry ,Article ,Gene Expression Regulation, Enzymologic ,Chromatin remodeling ,03 medical and health sciences ,Hydrolase ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Molecular Biology ,Cellular localization ,PARG ,Cell Death ,Chemistry ,Hydrolysis ,Cell Biology ,General Medicine ,Mitochondria ,Transport protein ,Enzyme Activation ,Oxidative Stress ,Protein Transport ,030104 developmental biology ,Multigene Family ,Proteolysis ,Protein Processing, Post-Translational ,DNA Damage ,Protein Binding - Abstract
Poly-ADP-ribosylation has been proposed to be a reversible protein modification, participating in diverse cellular functions including DNA repair, chromatin remodeling, genetic stability, mitosis, and cell death. Poly-ADP-ribosylation is initiated by the transfer of the ADP-ribose moiety of NAD+ primarily to the carboxyl groups of glutamate and aspartate and amino group of lysine residues in target proteins, followed by elongation of poly(ADP-ribose) (PAR) chains via α-O-glycosidic (C- 1"-C-2') ribose-ribose bonds. PAR consists of polymers of ADP-ribose (up to 200 units) with branching via α-O-glycosidic (C-1"'-C-2") ribose-ribose bonds. Further, the pyrophosphate group of each ADP-ribose has two negative charges. Therefore, in proteins modified by PAR, a complex structure with negative charges may lead to dynamic changes of functions. PAR formation is catalyzed by poly(ADP-ribose) polymerases (PARPs) and terminated by several types of enzymes with PAR-degrading activities; poly(ADP-ribose) glycohydrolase (PARG), ADP-ribosylacceptor hydrolase (ARH) 3, ARH1, and macrodomain-containing proteins. PARG has been thought to be primarily responsible for PAR degradation. In 2006, ARH3 was cloned and identified as another type of PAR-degrading protein. Although PAR-degrading activity of ARH3 is less than that of PARG, different mechanisms of PAR recognition and the cellular localization of ARH3 appear to be responsible for unique cellular roles of ARH3 involving PAR. In the present review, we focused on our findings regarding structure, biological properties, and cellular functions of ARH3. In addition, we describe the current knowledge of poly-ADP-ribosylation and cell death pathways regulated PARP1, PARG, and ARH3.
- Published
- 2016
148. Lymphangioleiomyomatosis
- Author
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Simon R. Johnson, Angelo M. Taveira-DaSilva, and Joel Moss
- Subjects
Sirolimus ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Antibiotics, Antineoplastic ,Lung Neoplasms ,Angiomyolipoma ,Pneumothorax ,Kidney Neoplasms ,Bronchodilator Agents ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Tuberous Sclerosis ,Humans ,Everolimus ,Lymphangioleiomyomatosis ,Tomography, X-Ray Computed ,Pleurodesis ,Ultrasonography - Abstract
Lymphangioleiomyomatosis is a rare multisystem disease predominantly affecting women that can occur sporadically or in association with tuberous sclerosis. Lung cysts progressively replace the lung parenchyma, which leads to dyspnea, recurrent pneumothorax, and in some cases respiratory failure. Patients may also have lymphatic disease in the thorax, abdomen, and pelvis, and renal angiomyolipomas. Treatment includes supportive care, bronchodilators, and for those with progressive disease, mammalian target of rapamycin (mTOR) inhibitors.
- Published
- 2016
149. The Arf GTPase-activating Protein, ASAP1, Binds Nonmuscle Myosin 2A to Control Remodeling of the Actomyosin Network
- Author
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Lisa M. Miller Jenkins, Attila Nagy, Sarah M. Heissler, James R. Sellers, Xiaoying Jian, Ruibai Luo, Pei-Wen Chen, Joel Moss, Kang Le, and Paul A. Randazzo
- Subjects
0301 basic medicine ,Biology ,Biochemistry ,Focal adhesion ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Myosin ,Animals ,Humans ,BAR domain ,Cytoskeleton ,Molecular Biology ,Actin ,Adaptor Proteins, Signal Transducing ,Gene knockdown ,Nonmuscle Myosin Type IIA ,Cell migration ,Actomyosin ,Cell Biology ,Protein Structure, Tertiary ,Cell biology ,030104 developmental biology ,NIH 3T3 Cells ,Signal transduction ,030217 neurology & neurosurgery ,HeLa Cells ,Protein Binding ,Signal Transduction - Abstract
ASAP1 regulates F-actin-based structures and functions, including focal adhesions (FAs) and circular dorsal ruffles (CDRs), cell spreading and migration. ASAP1 function requires its N-terminal BAR domain. We discovered that nonmuscle myosin 2A (NM2A) directly bound the BAR-PH tandem of ASAP1 in vitro. ASAP1 and NM2A co-immunoprecipitated and colocalized in cells. Knockdown of ASAP1 reduced colocalization of NM2A and F-actin in cells. Knockdown of ASAP1 or NM2A recapitulated each other's effects on FAs, cell migration, cell spreading, and CDRs. The NM2A-interacting BAR domain contributed to ASAP1 control of cell spreading and CDRs. Exogenous expression of NM2A rescued the effect of ASAP1 knockdown on CDRs but ASAP1 did not rescue NM2A knockdown defect in CDRs. Our results support the hypothesis that ASAP1 is a positive regulator of NM2A. Given other binding partners of ASAP1, ASAP1 may directly link signaling and the mechanical machinery of cell migration.
- Published
- 2016
150. Subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli induces stress granule formation
- Author
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Masatoshi Noda, Kinnosuke Yahiro, Kazuko Seto, Sayaka Nagasawa, Kimitoshi Ichimura, Joel Moss, Kohei Ogura, Sunao Iyoda, Makoto Ohnishi, and Hiroyasu Tsutsuki
- Subjects
0301 basic medicine ,Immunology ,Biology ,Cytoplasmic Granules ,Microbiology ,Article ,Gene Knockout Techniques ,eIF-2 Kinase ,03 medical and health sciences ,Stress granule ,Stress, Physiological ,Virology ,Humans ,Subtilisins ,Poly-ADP-Ribose Binding Proteins ,Protein kinase A ,Endoplasmic Reticulum Chaperone BiP ,Protein kinase C ,Shiga-Toxigenic Escherichia coli ,Escherichia coli Proteins ,Endoplasmic reticulum ,DNA Helicases ,Chloroquine ,Protein kinase R ,Molecular biology ,Protein Kinase C-delta ,RNA Recognition Motif Proteins ,030104 developmental biology ,Biochemistry ,Culture Media, Conditioned ,Host-Pathogen Interactions ,Unfolded protein response ,Caco-2 Cells ,Signal transduction ,Apoptosis Regulatory Proteins ,Carrier Proteins ,RNA Helicases ,HeLa Cells ,Signal Transduction ,Locus of enterocyte effacement - Abstract
Subtilase cytotoxin (SubAB) is mainly produced by locus of enterocyte effacement (LEE)-negative strains of Shiga-toxigenic Escherichia coli (STEC). SubAB cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress. This stress causes activation of ER stress sensor proteins and induction of caspase-dependent apoptosis. We found that SubAB induces stress granules (SG) in various cells. Aim of this study was to explore the mechanism by which SubAB induced SG formation. Here, we show that SubAB-induced SG formation is regulated by activation of double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). The culture supernatant of STEC O113:H21 dramatically induced SG in Caco2 cells, although subAB knockout STEC O113:H21 culture supernatant did not. Treatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and lysosomal inhibitors, NH(4)Cl and chloroquine, suppressed SubAB-induced SG formation, which was enhanced by PKC and PKD inhibitors. SubAB attenuated the level of PKD1 phosphorylation. Depletion of PKCδ and PKD1 by siRNA promoted SG formation in response to SubAB. Furthermore, death-associated protein 1 (DAP1) knockdown increased basal phospho-PKD1(S916) and suppressed SG formation by SubAB. However, SG formation by an ER stress inducer, Thapsigargin, was not inhibited in PMA-treated cells. Our findings show that SubAB-induced SG formation is regulated by the PERK/DAP1 signalling pathway, which may be modulated by PKCδ/PKD1, and different from the signal transduction pathway that results in Thapsigargin-induced SG formation.
- Published
- 2016
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