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    Asian society of gynecologic oncology international workshop 2018
    (2019-03-01) Tae Wook Kong; Hee Sug Ryu; Seung Cheol Kim; Takayuki Enomoto; Jin Li; Kenneth H. Kim; Seung Hyuk Shim; Peng Hui Wang; Suwanit Therasakvichya; Yusuke Kobayashi; Maria Lee; Tingyan Shi; Shin Wha Lee; Mikio Mikami; Satoru Nagase; Myong Cheol Lim; Jianliu Wang; Sarikapan Wilailak; Sang Wun Kim; Sook Hee Hong; David S.P. Tan; Masaki Mandai; Suk Joon Chang; Ruby Yun Ju Huang; Kimio Ushijima; Jung Yun Lee; Xiaojun Chen; Kazunori Ochiai; Taek Sang Lee; Bingyi Yang; Farhana Kalam; Qiaoying Lv; Mohd Faizal Ahmad; Muhammad Rizki Yaznil; Kanika Batra Modi; Manatsawee Manopunya; Dae Hoon Jeong; Arb Aroon Lertkhachonsuk; Hyun Hoon Chung; Hidemichi Watari; Seob Jeon; Peking University People's Hospital; Graduate School of Medicine; Fudan University Shanghai Cancer Center; Cancer Science Institute of Singapore; Inje University Paik Hospital; Universitas Sumatera Utara; National Cancer Center, Gyeonggi; The Jikei University School of Meidicine; National University Hospital, Singapore; Ewha Womans University School of Medicine; Ajou University, School of Medicine; Hokkaido University School of Medicine; Niigata University School of Medicine; The University of Alabama at Birmingham; Keio University School of Medicine; Soonchunhyang University, College of Medicine; Yonsei University College of Medicine; Yamagata University; Faculty of Medicine, Ramathibodi Hospital, Mahidol University; Konkuk University, College of Medicine; Veterans General Hospital-Taipei; Faculty of Medicine, Siriraj Hospital, Mahidol University; Tokai University; Fudan University; University of Ulsan, College of Medicine; The Catholic University of Korea; Universiti Kebangsaan Malaysia; Kurume University School of Medicine; Chiang Mai University; Seoul National University College of Medicine; Max Institute of Cancer Care; National Institute of Cancer Research and Hospital
    © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology. The Asian Society of Gynecologic Oncology International Workshop 2018 on gynecologic oncology was held in the Ajou University Hospital, Suwon, Korea on the 24th to 25th August 2018. The workshop was an opportunity for Asian doctors to discuss the latest findings of gynecologic cancer, including cervical, ovarian, and endometrial cancers, as well as the future of fertility-sparing treatments, minimally invasive/radical/debulking surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Clinical guidelines and position statement of Asian countries were presented by experts. Asian clinical trials for gynecologic cancers were reviewed and experts emphasized the point that original Asian study is beneficial for Asian patients. In Junior session, young gynecologic oncologists presented their latest research on gynecologic cancers.
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    Biotinylated Streptavidin Surface Coating Improves the Efficacy of a PLGA Microparticle-Based Cancer Vaccine
    (2020-09-16) Brett P. Gross; Khanidtha Chitphet; Amaraporn Wongrakpanich; Emad I. Wafa; Lyse A. Norian; Aliasger K. Salem; The University of Alabama at Birmingham; University of Iowa; Mahidol University
    Triple-negative breast cancer (TNBC) is an immune-enriched subset of breast cancer that has recently demonstrated clinical responsiveness to combinatorial immunotherapy. However, the lack of targeted interventions against hormone receptors or HER2 continues to limit treatment options for these patients. To begin expanding available interventions for patients with metastatic TNBC, we previously reported a therapeutic vaccine regimen that significantly reduced spontaneous lung metastases in a preclinical TNBC model. This heterologous vaccine approach "primed" mice with tumor lysate antigens encapsulated within poly(lactic-co-glycolic) acid microparticles (PLGA MPs), and then "boosted" mice with tumor lysates plus adjuvant. The use of the PLGA MP prime as monotherapy demonstrated no efficacy, suggesting that improving this component of our therapy would achieve greater vaccine efficacy. Here, we functionally improved the PLGA MP prime by coating microparticles with biotinylated streptavidin-conjugated using 1-ethyl-3-(3-dimethylaminoproplyl) carbodiimide/N-hydroxysuccinimide (EDC/Sulfo-NHS) linkers. This modification enhanced the immunostimulatory potential of our PLGA MPs, as evidenced by increased phagocytosis, maturation, and stimulatory ligand expression by antigen-presenting cells (APCs). Therapeutic prime/boost vaccination of TNBC-bearing mice with surfaced-coated PLGA MPs significantly reduced spontaneous lung metastases by an average of 56% relative to mice primed with unmodified PLGA MPs, and a significant 88% average reduction in spontaneous lung metastases relative to untreated control mice. These findings illustrate that relatively common biotin-streptavidin conjugation formulations can positively affect microparticle-based vaccine immunogenicity resulting in enhanced therapeutic efficacy against established preclinical mammary tumors.
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    CYP11A1-derived vitamin D3 products protect against UVB-induced inflammation and promote keratinocytes differentiation
    (2020-08-01) Anyamanee Chaiprasongsuk; Zorica Janjetovic; Tae Kang Kim; Robert C. Tuckey; Wei Li; Chander Raman; Uraiwan Panich; Andrzej T. Slominski; Birmingham VA Medical Center; University of Western Australia; The University of Alabama at Birmingham; Faculty of Medicine, Siriraj Hospital, Mahidol University; University of Tennessee Health Science Center; Chulabhorn Royal Academy
    © 2020 UVB radiation mediates inflammatory responses causing skin damage and defects in epidermal differentiation. 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) interacts with the vitamin D3 receptor (VDR) to regulate inflammatory responses. Additionally, 1,25(OH)2D3/VDR signaling represents a potential therapeutic target in the treatment of skin disorders associated with inflammation and poor differentiation of keratinocytes. Since the protective effect of 1,25(OH)2D3 against UVB-induced skin damage and inflammation is recognized, CYP11A1-derived vitamin D3-hydroxyderivatives including 20(OH)D3, 1,20(OH)2D3, 20,23(OH)2D3 and 1,20,23(OH)3D3 were tested for their anti-inflammatory and skin protection properties in UVB-irradiated human epidermal keratinocytes (HEKn). HEKn were treated with secosteroids for 24 h pre- and post-UVB (50 mJ/cm2) irradiation. Secosteroids modulated the expression of the inflammatory response genes (IL-17, NF-κB p65, and IκB-α), reducing nuclear-NF-κB-p65 activity and increasing cytosolic-IκB-α expression as well as that of pro-inflammatory mediators, IL-17, TNF-α, and IFN-γ. They stimulated the expression of involucrin (IVL) and cytokeratin 10 (CK10), the major markers of epidermal differentiation, in UVB-irradiated cells. We conclude that CYP11A1-derived hydroxyderivatives inhibit UVB-induced epidermal inflammatory responses through activation of IκB-α expression and suppression of NF-kB-p65 activity and its downstream signaling cytokines, TNF-α, and IFN-γ, as well as by inhibiting IL-17 production and activating epidermal differentiation.
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    CYP27A1 acts on the pre-vitamin D3 photoproduct, lumisterol, producing biologically active hydroxy-metabolites
    (2018-07-01) Robert C. Tuckey; Wei Li; Dejian Ma; Chloe Y.S. Cheng; Katie M. Wang; Tae Kang Kim; Saowanee Jeayeng; Andrzej T. Slominski; Birmingham VA Medical Center; University of Western Australia; The University of Alabama at Birmingham; Faculty of Medicine, Siriraj Hospital, Mahidol University; University of Tennessee Health Science Center
    © 2018 Elsevier Ltd Prolonged exposure of the skin to UV radiation causes previtamin D3, the initial photoproduct formed by opening of the B ring of 7-dehydrocholesterol, to undergo a second photochemical reaction where the B-ring is reformed giving lumisterol3 (L3), a stereoisomer of 7-dehydrocholesterol. L3 was believed to be an inactive photoproduct of excessive UV radiation whose formation prevents excessive vitamin D production. Recently, we reported that L3 is present in serum and that CYP11A1 can act on L3 producing monohydroxy- and dihydroxy-metabolites which inhibit skin cell proliferation similarly to 1α,25-dihydroxyvitamin D3. In this study we tested the ability of human CYP27A1 to hydroxylate L3. L3 was metabolized by purified CYP27A1 to 3 major products identified as 25-hydroxyL3, (25R)-27-hydroxyL3 and (25S)-27-hydroxyL3, by NMR. These three products were also seen when mouse liver mitochondria containing CYP27A1 were incubated with L3. The requirement for CYP27A1 for their formation by mitochondria was confirmed by the inhibition of their synthesis by 5β-cholestane-3α,7α,12α-triol, an intermediate in bile acid synthesis which serves as an efficient competitive substrate for CYP27A1. CYP27A1 displayed a high k cat for the metabolism of L3 (76 mol product/min/mol CYP27A1) and a catalytic efficiency (k cat /K m ) that was 260-fold higher than that for vitamin D3. The CYP27A1-derived hydroxy-derivatives inhibited the proliferation of cultured human melanoma cells and colony formation with IC 50 values in the nM range. Thus, L3 is metabolized efficiently by CYP27A1 with hydroxylation at C25 or C27 producing metabolites potent in their ability to inhibit melanoma cell proliferation, supporting that L3 is a prohormone which can be activated by CYP-dependent hydroxylations.
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    Editorial: Redox Biology of Skin Aging and Carcinogenesis: the Role of Natural Antioxidants as Potential Protective Agents
    (2020-03-06) Uraiwan Panich; Andrzej T. Slominski; Birmingham VA Medical Center; The University of Alabama at Birmingham; Faculty of Medicine, Siriraj Hospital, Mahidol University
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    European Position Paper on Rhinosinusitis and Nasal Polyps 2020
    (2020-02-20) W. J. Fokkens; V. J. Lund; C. Hopkins; P. W. Hellings; R. Kern; S. Reitsma; S. Toppila-Salmi; M. Bernal-Sprekelsen; J. Mullol; I. Alobid; W. Terezinha Anselmo-Lima; C. Bachert; F. Baroody; C. von Buchwald; A. Cervin; N. Cohen; J. Constantinidis; L. De Gabory; M. Desrosiers; Z. Diamant; R. G. Douglas; P. H. Gevaert; A. Hafner; R. J. Harvey; G. F. Joos; L. Kalogjera; A. Knill; J. H. Kocks; B. N. Landis; J. Limpens; S. Lebeer; O. Lourenco; C. Meco; P. M. Matricardi; L. O'Mahony; C. M. Philpott; D. Ryan; R. Schlosser; B. Senior; T. L. Smith; T. Teeling; P. V. Tomazic; D. Y. Wang; D. Wang; L. Zhang; A. M. Agius; C. Ahlstrom-Emanuelsson; R. Alabri; S. Albu; S. Alhabash; A. Aleksic; M. Aloulah; M. Al-Qudah; S. Alsaleh; M. A. Baban; T. Baudoin; T. Balvers; P. Battaglia; J. D. Bedoya; A. Beule; K. M. Bofares; I. Braverman; E. Brozek-Madry; B. Richard; C. Callejas; S. Carrie; L. Caulley; D. Chussi; E. de Corso; A. Coste; U. El Hadi; A. Elfarouk; P. H. Eloy; S. Farrokhi; G. Felisati; M. D. Ferrari; R. Fishchuk; W. Grayson; P. M. Goncalves; B. Grdinic; V. Grgic; A. W. Hamizan; J. V. Heinichen; S. Husain; T. I. Ping; J. Ivaska; F. Jakimovska; L. Jovancevic; E. Kakande; R. Kamel; S. Karpischenko; H. H. Kariyawasam; H. Kawauchi; A. Kjeldsen; L. Klimek; A. Krzeski; G. Kopacheva Barsova; S. W. Kim; D. Lal; J. J. Letort; Klinički Bolnički Centar Sestre Milosrdnice; CHU UCL Namur; University of East Anglia, Norwich Medical School; Edinburgh Medical School; Hospital de Clínicas; University of Banja Luka; Sveučilište u Zagrebu, Farmaceutsko Biokemijski Fakultet; Skin and Allergy Hospital; University of Sulaimaniya; Fondazione Policlinico Universitario Agostino Gemelli IRCCS Università Cattolica del Sacro Cuore; Beijing Tongren Hospital, Capital Medical University; L-Università ta' Malta; SS Cyril and Methodius University; Omar Al-Mukhtar University; Sultan Qaboos University; Makerere University; Kilimanjaro Christian Medical College; Medical University of Warsaw; University of Novi Sad; American University of Beirut; University Hospital of Ghent; Vilniaus universitetas; Universidad de Antioquia; Jordan University of Science and Technology; Universiteit Gent; KU Leuven– University Hospital Leuven; The University of Queensland; Københavns Universitet; Università degli Studi di Milano; Royal National Throat, Nose and Ear Hospital; Pontificia Universidad Católica de Chile; Lunds Universitet; University of Ottawa, Canada; Royal Brisbane and Women's Hospital; Stockholms universitet; Hille Yaffe Medical Center Israel; The University of Alabama at Birmingham; Mayo Clinic Scottsdale-Phoenix, Arizona; Yong Loo Lin School of Medicine; Shimane University; Charité – Universitätsmedizin Berlin; University College Cork; Université Paris-Est Créteil; Universiti Malaysia Sarawak; Medical University of South Carolina; University of Chicago Medicine Comer Children's Hospital; UNC School of Medicine; Macquarie University; Syddansk Universitet; Oregon Health & Science University; Charles University; Leiden University Medical Center - LUMC; Bushehr University of Medical Sciences; Aristotle University of Thessaloniki; Paracelsus Medizinische Privatuniversitat; Skånes universitetssjukhus; Northwestern University Feinberg School of Medicine; King Saud University; Universitatea de Medicina si Farmacie Iuliu Hatieganu din Cluj-Napoca; Universiteit Antwerpen; Ankara Üniversitesi; Cairo University; Hôpitaux universitaires de Genève; Fudan University; University of Montreal; Universidade de Sao Paulo - USP; Universitätsklinikum Münster; University of Zagreb School of Medicine; Medizinische Universität Graz; Newcastle University, United Kingdom; University of Auckland; Guy's and St Thomas' NHS Foundation Trust; Università degli Studi dell'Insubria; University of Pennsylvania Perelman School of Medicine; Groupe Hospitalier Pellegrin; Pavlov University; University of Valencia; Universiteit van Amsterdam; Kyung Hee University; Universiti Kebangsaan Malaysia; Universitat de Barcelona; James Paget University Hospitals NHS Foundation Trust; Universidade da Beira Interior; Director of Saint Petersburg Research Institute of Ear, Throat, Nose and Speech; ENT Department; Persian Gulf Tropical Medicine Research Center; University If Medicine; Research Director Respiratory and Allergy; Central city clinical hospital of lvano-Frankivsk city council; Pontifical University Catholic of Ecuador; Centro Hospitalar de Entre Douro e Vouga; Patient representative; Zagreb University School of Medicine; Observational and Pragmatic Research Institute; Patient Representative; Center for Rhinology and Allergology; Optimum Patient Care; Mulago National Referral Hospital; General Hospital; Roy. Nat. ENT Hosp.
    The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
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    Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: A clinical trial
    (2018-07-01) Melanie Royce; Thomas Bachelot; Cristian Villanueva; Mustafa Özgüroglu; Sergio J. Azevedo; Felipe Melo Cruz; Marc Debled; Roberto Hegg; Tatsuya Toyama; Carla Falkson; Joon Jeong; Vichien Srimuninnimit; William J. Gradishar; Christina Arce; Antonia Ridolfi; Chinjune Lin; Fatima Cardoso; Champalimaud Foundation; Yonsei University Health System; University of New Mexico; Istanbul Üniversitesi; Centre Hospitalier Universitaire de Besancon; The University of Alabama at Birmingham; Le Centre Régional de Lutte Contre le Cancer Léon Bérard; Hospital de Clinicas de Porto Alegre; Novartis Pharma S.A.S.; Northwestern University Feinberg School of Medicine; Faculty of Medicine, Siriraj Hospital, Mahidol University; Universidade de Sao Paulo - USP; Institut Bergonie; Nagoya University; Novartis Pharmaceuticals Corporation; Instituto Brasileiro de Controle do Câncer
    © 2018 American Medical Association. IMPORTANCE Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. OBJECTIVE To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. DESIGN, SETTING, AND PARTICIPANTS In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). INTERVENTIONS Patients received first-line treatment with everolimus, 10mg/d, plus letrozole, 2.5mg/d. Second-line treatment with everolimus, 10mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. MAIN OUTCOMES AND MEASURES The primary end pointwas investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. RESULTS A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95%CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7%(95%CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95%CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). CONCLUSIONS AND RELEVANCE The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
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    Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1
    (2021-01-01) Daniel J. Klionsky; Amal Kamal Abdel-Aziz; Sara Abdelfatah; Mahmoud Abdellatif; Asghar Abdoli; Steffen Abel; Hagai Abeliovich; Marie H. Abildgaard; Yakubu Princely Abudu; Abraham Acevedo-Arozena; Iannis E. Adamopoulos; Khosrow Adeli; Timon E. Adolph; Annagrazia Adornetto; Elma Aflaki; Galila Agam; Anupam Agarwal; Bharat B. Aggarwal; Maria Agnello; Patrizia Agostinis; Javed N. Agrewala; Alexander Agrotis; Patricia V. Aguilar; S. Tariq Ahmad; Zubair M. Ahmed; Ulises Ahumada-Castro; Sonja Aits; Shu Aizawa; Yunus Akkoc; Tonia Akoumianaki; Hafize Aysin Akpinar; Ahmed M. Al-Abd; Lina Al-Akra; Abeer Al-Gharaibeh; Moulay A. Alaoui-Jamali; Simon Alberti; Elísabet Alcocer-Gómez; Cristiano Alessandri; Muhammad Ali; M. Abdul Alim Al-Bari; Saeb Aliwaini; Javad Alizadeh; Eugènia Almacellas; Alexandru Almasan; Alicia Alonso; Guillermo D. Alonso; Nihal Altan-Bonnet; Dario C. Altieri; Élida M.C. Álvarez; Sara Alves; Cristine Alves da Costa; Mazen M. Alzaharna; Marialaura Amadio; Consuelo Amantini; Cristina Amaral; Susanna Ambrosio; Amal O. Amer; Veena Ammanathan; Zhenyi An; Stig U. Andersen; Shaida A. Andrabi; Magaiver Andrade-Silva; Allen M. Andres; Sabrina Angelini; David Ann; Uche C. Anozie; Mohammad Y. Ansari; Pedro Antas; Adam Antebi; Zuriñe Antón; Tahira Anwar; Lionel Apetoh; Nadezda Apostolova; Toshiyuki Araki; Yasuhiro Araki; Kohei Arasaki; Wagner L. Araújo; Jun Araya; Catherine Arden; Maria Angeles Arévalo; Sandro Arguelles; Esperanza Arias; Jyothi Arikkath; Hirokazu Arimoto; Aileen R. Ariosa; Darius Armstrong-James; Laetitia Arnauné-Pelloquin; Angeles Aroca; Daniela S. Arroyo; Ivica Arsov; Rubén Artero; Dalia Maria Lucia Asaro; Michael Aschner; Milad Ashrafizadeh; Osnat Ashur-Fabian; Atanas G. Atanasov; Alicia K. Au; Patrick Auberger; Holger W. Auner; Laure Aurelian; Departement Cellulaire en Moleculaire Geneeskunde; Université Côte d'Azur; The Francis Crick Institute; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Indian Institute of Technology Ropar; Centre du Cancer Segal; Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences; Universidade Nove de Julho; TIGEM Telethon Institute of Genetics and Medicine; Biotech Research & Innovation Centre; Islamic University of Gaza; Gulf Medical University; Universidad de Sevilla; NOVA Medical School - Faculdade de Ciências Médicas, Universidade Nova de Lisboa; Tokyo University of Pharmacy and Life Sciences; Stanford University School of Medicine; Sapienza Università di Roma; The Jikei University School of Medicine; Johannes Gutenberg-Universität Mainz; Istituto Europeo di Oncologia; Aarhus Universitet; Alma Mater Studiorum Università di Bologna; Universidad del Pais Vasco; Universite Paul Sabatier Toulouse III; Ben-Gurion University of the Negev; The University of Alabama at Birmingham; Università degli Studi di Camerino; Universität Wien; University of Michigan, Ann Arbor; The University of Sydney; Osaka University; University of Cologne; University of California, San Francisco; UC Davis School of Medicine; National Institute of Neuroscience, Kodaira; CSIC - Instituto Cajal (IC); Leibniz Institut fur Pflanzenbiochemie; UiT The Arctic University of Norway; Cleveland Clinic Foundation; University of Bristol; Imperial College Faculty of Medicine; Università della Calabria; Rajshahi University; Institutionen för Experimentell Medicinsk Vetenskap; Technische Universität Dresden; Kræftens Bekæmpelse; Università degli Studi di Palermo; University of Toronto; Ain Shams University; Cedars-Sinai Medical Center; Wilmer Eye Institute; Medical Research Council; The University of Tennessee, Knoxville; Università degli Studi di Pavia; Universidade Federal de São Paulo; UT Medical Branch at Galveston; Universidade Federal de Vicosa; University of Maryland School of Medicine; University of Crete Medical School; Hospital Universitari de Bellvitge; Medizinische Universität Wien; Max Rady College of Medicine, University of Manitoba; The Wistar Institute; The Institute of Cancer Research; Sabancı Üniversitesi; University of Dundee; Tohoku University; Medizinische Universitat Innsbruck; Howard University College of Medicine; Hebrew University of Jerusalem; National Eye Institute (NEI); City of Hope National Med Center; Universidade do Porto; City University of New York; Safar Center for Resuscitation Research; Koç Üniversitesi; Medizinische Universität Graz; Newcastle University; Universidad Mayor; Colby College; Tel Aviv University; Pasteur Institute of Iran; National Heart, Lung, and Blood Institute (NHLBI); Iowa State University; The Ohio State University; Universidad de la Laguna; Helsingin Yliopisto; Universitat de València; Nihon University; Albert Einstein College of Medicine of Yeshiva University; Universitat de Barcelona; Universidad de Buenos Aires; Northeastern Ohio Universities Colleges of Medicine and Pharmacy; Inserm; Universidad Nacional de Córdoba; Save as Ravi Manjithaya; Interdisciplinary Research Structure for Biotechnology and Biomedicine (ERI BIOTECMED); Inflammation Research Center
    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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    Hydroxylumisterols, photoproducts of pre-vitamin d3, protect human keratinocytes against uvb-induced damage
    (2020-12-02) Anyamanee Chaiprasongsuk; Zorica Janjetovic; Tae Kang Kim; Cynthia J. Schwartz; Robert C. Tuckey; Edith K.Y. Tang; Chander Raman; Uraiwan Panich; Andrzej T. Slominski; Birmingham VA Medical Center; The University of Western Australia; The University of Alabama at Birmingham; Faculty of Medicine, Siriraj Hospital, Mahidol University; Chulabhorn Royal Academy
    © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
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    Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial
    (2019-03-01) Gil I. Wolfe; Henry J. Kaminski; Inmaculada B. Aban; Greg Minisman; Hui Chien Kuo; Alexander Marx; Philipp Ströbel; Claudio Mazia; Joel Oger; J. Gabriel Cea; Jeannine M. Heckmann; Amelia Evoli; Wilfred Nix; Emma Ciafaloni; Giovanni Antonini; Rawiphan Witoonpanich; John O. King; Said R. Beydoun; Colin H. Chalk; Alexandru C. Barboi; Anthony A. Amato; Aziz I. Shaibani; Bashar Katirji; Bryan R.F. Lecky; Camilla Buckley; Angela Vincent; Elza Dias-Tosta; Hiroaki Yoshikawa; Márcia Waddington-Cruz; Michael T. Pulley; Michael H. Rivner; Anna Kostera-Pruszczyk; Robert M. Pascuzzi; Carlayne E. Jackson; Jan J.G.M. Verschuuren; Janice M. Massey; John T. Kissel; Lineu C. Werneck; Michael Benatar; Richard J. Barohn; Rup Tandan; Tahseen Mozaffar; Nicholas J. Silvestri; Robin Conwit; Joshua R. Sonett; Alfred Jaretzki; John Newsom-Davis; Gary R. Cutter; Gary Cutter; Inmaculada Aban; Michelle Feese; Gil Wolfe; Henry Kaminski; Joshua Sonett; Valeria Saluto; Moises Rosenberg; Valeria Alvarez; Lisa Rey; John King; Helmut Butzkueven; John Goldblatt; John Carey; John Pollard; Stephen Reddel; Nicholas Handel; Brian McCaughan; Linda Pallot; Ricardo Novis; Carlos Boasquevisque; Rubens Morato-Fernandez; Manoel Ximenes; Lineu Werneck; Rosana Scola; Paulo Soltoski; Colin Chalk; Fraser Moore; David Mulder; Lisa Wadup; Michele Mezei; Kenneth Evans; Theresa Jiwa; Anne Schaffar; Chris White; Cory Toth; Gary Gelfand; Susan Wood; Elizabeth Pringle; Jocelyn Zwicker; Donna Maziak; Farid Shamji; Sudhir Sundaresan; Andrew Seely; Gabriel Cea; Renato Verduga; Alberto Aguayo; Sebastian Jander; Philipp Zickler; Michael Klein; Cleo Aron Weis; Arthur Melms; Duke University Medical Center; Augusta University; Medical University of Warsaw; Hospital de Base do Distrito Federal; Università degli Studi di Roma La Sapienza; University at Buffalo, State University of New York; Università Cattolica del Sacro Cuore, Rome; University of Vermont College of Medicine; Universität Göttingen; Johannes Gutenberg Universität Mainz; University of Southern California; Columbia University Irving Medical Center; The University of Alabama at Birmingham; University of Oxford; University of Melbourne; School of Medicine and Health Sciences; Kanazawa University; University of Rochester Medical Center; Indiana University School of Medicine Indianapolis; University of Miami Leonard M. Miller School of Medicine; Walton Centre for Neurology and Neurosurgery NHS Trust; University of Texas Health Science Center at San Antonio; Leiden University Medical Center - LUMC; Universidade Federal do Parana; University of Florida; National Institute of Neurological Disorders and Stroke; Mahidol University; Medical College of Wisconsin; Universidad de Chile; The University of British Columbia; University of Kansas Medical Center; University of California, Irvine; Ohio State University; Harvard Medical School; McGill University; Universitätsklinikum Mannheim; Universidad de Buenos Aires; University of Cape Town; Case Western Reserve University; Universidade Federal do Rio de Janeiro; Nerve and Muscle Center of Texas
    © 2019 Elsevier Ltd Background: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke.
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    Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo
    (2018-09-01) Cezary Skobowiat; Anna A. Brożyna; Zorica Janjetovic; Saowanee Jeayeng; Allen S.W. Oak; Tae Kang Kim; Uraiwan Panich; Russel J. Reiter; Andrzej T. Slominski; Birmingham VA Medical Center; Regional Oncology Centre, Bydgoszcz; The University of Alabama at Birmingham; Ludwik Rydygier Collegium Medicum in Bydgoszcz; Faculty of Medicine, Siriraj Hospital, Mahidol University
    © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Melatonin and its derivatives (N1-acetyl-N2-formyl-5-methoxykynurenine [AFMK] and N-acetyl serotonin [NAS]) have broad-spectrum protective effects against photocarcinogenesis, including both direct and indirect antioxidative actions, regulation of apoptosis and DNA damage repair; these data were primarily derived from in vitro models. This study evaluates possible beneficial effects of melatonin and its active derivatives against ultraviolet B (UVB)-induced harm to human and porcine skin ex vivo and to cultured HaCaT cells. The topical application of melatonin, AFMK, or NAS protected epidermal cells against UVB-induced 8-OHdG formation and apoptosis with a further increase in p53ser15 expression, especially after application of melatonin or AFMK but not after NAS use. The photoprotective action was observed in pre- and post-UVB treatment in both human and porcine models. Melatonin along with its derivatives upregulated also the expression of antioxidative enzymes after UVB radiation of HaCaT cells. The exogenous application of melatonin or its derivatives represents a potent and promising tool for preventing UVB-induced oxidative stress and DNA damage. This protection results in improved genomic, cellular, and tissue integrity against UVB-induced carcinogenesis, especially when applied prior to UV exposure. In addition, our ex vivo experiments provide fundamental justification for further testing the clinical utility of melatonin and metabolites as protectors again UVB in human subjects. Our ex vivo data constitute the bridge between vitro to vivo translation and thus justifies the pursue for further clinical utility of melatonin in maintaining skin homeostasis.
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    Pharmacokinetics and safety of maraviroc in neonates
    (2021-03-01) Julia C. Rosebush; Brookie M. Best; Ellen G. Chadwick; Kevin Butler; John Moye; Elizabeth Smith; Sarah Bradford; Christina A. Reding; Sisinyana R. Mathiba; Sherika Hanley; Mariam Aziz; James Homans; Edward P. Acosta; William Murtaugh; Manoli Vourvahis; Lynn McFadyen; Katy Hayward; Mark Mirochnick; Pearl Samson; Ntatule Hilda Ndiweni; Zaakirah Essack; Mandisa Nyati; Lorna Pillay; Rosemary Gazu; Natasha Pillay; Damien Sookoo; Kulkanya Chokephaibulkit; Supattra Rungmaitree; Keswadee Lapphra; Orasri Wittawatmongkol; Isaac Tsikhutsu; Edner Openda; Priscillah Bii; David Wekulo; Ellen Chadwick; Jessica D’Angelo; Margaret Ann Sanders; Alice Stek; Mikhaela Cielo; La Shonda Spencer; Yvonne Morales; Christiana Smith-Anderson; Kacey Navarro; Carrie Glenny; Elizabeth McFarland; R. N. Maureen McNichols; Julie Schmidt; Helen Cejtin; Ixchell Ortiz-Estes; Katherine Knapp; Nehali Patel; Patricia M. Flynn; Jill Utech; Kathleen George; Shane Reynolds; Terence Fenton; Michelle Hsu; Jamie Branco-Ricard; Victoria Wong; Barbara Heckman; Kyle Whitson; Shawn Ward; Navdeep K. Thoofer; Siriraj Hospital; FHI 360; ViiV Healthcare; Pfizer Limited, UK; Frontier Science & Technology Research Foundation, Inc.; Kenya Medical Research Institute; Harvard T.H. Chan School of Public Health; University of California, San Diego; University of Southern California; The University of Chicago; The University of Alabama at Birmingham; Children's Hospital Los Angeles; St. Jude Children's Research Hospital; Boston University; Rush University Medical Center; National Institute of Allergy and Infectious Diseases (NIAID); Ann & Robert H. Lurie Children's Hospital of Chicago; University of the Witwatersrand, Johannesburg; University of KwaZulu-Natal; National Institutes of Health (NIH); Rush University; IMPAACT Statistical and Data Analysis Center; IMPAACT Data Management Center; IMPAACT Laboratory Center; CAPRISA Umlazi Clinical Research Site; IMPAACT Operations Center; University of Colorado; Ann and Robert H. Lurie Children's Hospital of Chicago; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Pfizer Global Research and Development
    Objective: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. Design: A phase I, multicentre, open-label study enrolling two sequential cohorts. Methods: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety. Results: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17–33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3þ toxicities, early study or treatment discontinuations due to maraviroc occurred. Conclusion: Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/ intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.
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    Photoprotective Properties of Vitamin D and Lumisterol Hydroxyderivatives
    (2020-01-01) Andrzej T. Slominski; Anyamanee Chaiprasongsuk; Zorica Janjetovic; Tae Kang Kim; Joanna Stefan; Radomir M. Slominski; Vidya Sagar Hanumanthu; Chander Raman; Shariq Qayyum; Yuwei Song; Yuhua Song; Uraiwan Panich; David K. Crossman; Mohammad Athar; Michael F. Holick; Anton M. Jetten; Michal A. Zmijewski; Jaroslaw Zmijewski; Robert C. Tuckey; Birmingham VA Medical Center; University of Western Australia; National Institute of Environmental Health Sciences; The University of Alabama at Birmingham; Boston University; Gdanski Uniwersytet Medyczny; Faculty of Medicine, Siriraj Hospital, Mahidol University; Chulabhorn Royal Academy
    © 2020, Springer Science+Business Media, LLC, part of Springer Nature. We have previously described new pathways of vitamin D3 activation by CYP11A1 to produce a variety of metabolites including 20(OH)D3 and 20,23(OH)2D3. These can be further hydroxylated by CYP27B1 to produce their C1α-hydroxyderivatives. CYP11A1 similarly initiates the metabolism of lumisterol (L3) through sequential hydroxylation of the side chain to produce 20(OH)L3, 22(OH)L3, 20,22(OH)2L3 and 24(OH)L3. CYP11A1 also acts on 7-dehydrocholesterol (7DHC) producing 22(OH)7DHC, 20,22(OH)27DHC and 7-dehydropregnenolone (7DHP) which can be converted to the D3 and L3 configurations following exposure to UVB. These CYP11A1-derived compounds are produced in vivo and are biologically active displaying anti-proliferative, anti-inflammatory, anti-cancer and pro-differentiation properties. Since the protective role of the classical form of vitamin D3 (1,25(OH)2D3) against UVB-induced damage is recognized, we recently tested whether novel CYP11A1-derived D3- and L3-hydroxyderivatives protect against UVB-induced damage in epidermal human keratinocytes and melanocytes. We found that along with 1,25(OH)2D3, CYP11A1-derived D3-hydroxyderivatives and L3 and its hydroxyderivatives exert photoprotective effects. These included induction of intracellular free radical scavenging and attenuation and repair of DNA damage. The protection of human keratinocytes against DNA damage included the activation of the NRF2-regulated antioxidant response, p53-phosphorylation and its translocation to the nucleus, and DNA repair induction. These data indicate that novel derivatives of vitamin D3 and lumisterol are promising photoprotective agents. However, detailed mechanisms of action, and the involvement of specific nuclear receptors, other vitamin D binding proteins or mitochondria, remain to be established.
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    Properties of purified CYP2R1 in a reconstituted membrane environment and its 25-hydroxylation of 20-hydroxyvitamin D3
    (2018-03-01) Chloe Y.S. Cheng; Tae Kang Kim; Saowanee Jeayeng; Andrzej T. Slominski; Robert C. Tuckey; Birmingham VA Medical Center; University of Western Australia; The University of Alabama at Birmingham; Faculty of Medicine, Siriraj Hospital, Mahidol University
    © 2017 Elsevier Ltd Recent studies indicate that CYP2R1 is the major 25-hydroxylase catalyzing the first step in vitamin D activation. Since the catalytic properties of CYP2R1 have been poorly studied to date and it is a membrane protein, we examined the purified enzyme in a membrane environment. CYP2R1 was expressed in E. coli and purified by nickel affinity- and hydrophobic interaction-chromatography and assayed in a reconstituted membrane system comprising phospholipid vesicles plus purified human NADPH-P450 oxidoreductase. CYP2R1 converted vitamin D3 in the vesicle membrane to 25-hydroxyvitamin D3 [25(OH)D3] with good adherence to Michaelis-Menten kinetics. The kinetic parameters for 25-hydroxylation of vitamin D3 by the two major vitamin D 25-hydroxylases, CYP2R1 and CYP27A1, were examined in vesicles under identical conditions. CYP2R1 displayed a slightly lower k cat than CYP27A1 but a much lower K m for vitamin D3, and thus an overall 17-fold higher catalytic efficiency (k cat /K m ), consistent with CYP2R1 being the major vitamin D 25-hydroxylase. 20-Hydroxyvitamin D3 [20(OH)D3], the main product of vitamin D3 activation by an alternative pathway catalyzed by CYP11A1, was metabolized by CYP2R1 to 20,25-dihydroxyvitamin D3 [20,25(OH) 2 D3], with catalytic efficiency similar to that for the 25-hydroxylation of vitamin D3. 20,25(OH) 2 D3 retained full, or somewhat enhanced activity compared to the parent 20(OH)D3 for the inhibition of the proliferation of melanocytes and dermal fibroblasts, with a potency comparable to 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D3]. The 20,25(OH) 2 D3 was also able to act as an inverse agonist on retinoic acid-related orphan receptor α, like its parent 20(OH)D3. Thus, the major findings of this study are that CYP2R1 can metabolize substrates in a membrane environment, the enzyme displays higher catalytic efficiency than CYP27A1 for the 25-hydroxylation of vitamin D, it efficiently hydroxylates 20(OH)D3 at C25 and this product retains the biological activity of the parent compound.
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    Protective effects of novel derivatives of vitamin D 3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and p53 defense mechanisms
    (2019-06-01) Anyamanee Chaiprasongsuk; Zorica Janjetovic; Tae Kang Kim; Stuart G. Jarrett; John A. D'Orazio; Michael F. Holick; Edith K.Y. Tang; Robert C. Tuckey; Uraiwan Panich; Wei Li; Andrzej T. Slominski; Birmingham VA Medical Center; University of Western Australia; University of Kentucky HealthCare; The University of Alabama at Birmingham; Boston University; Faculty of Medicine, Siriraj Hospital, Mahidol University; University of Tennessee Health Science Center
    © 2019 We tested whether novel CYP11A1-derived vitamin D 3 - and lumisterol-hydroxyderivatives, including 1,25(OH) 2 D 3 , 20(OH)D 3 , 1,20(OH) 2 D 3 , 20,23(OH) 2 D 3 , 1,20,23(OH) 3 D 3 , lumisterol, 20(OH)L 3 , 22(OH)L 3 , 20,22(OH) 2 L 3 , and 24(OH)L 3 , can protect against UVB-induced damage in human epidermal keratinocytes. Cells were treated with above compounds for 24 h, then subjected to UVB irradiation at UVB doses of 25, 50, 75, or 200 mJ/cm 2 , and then examined for oxidant formation, proliferation, DNA damage, and the expression of genes at the mRNA and protein levels. Oxidant formation and proliferation were determined by the DCFA-DA and MTS assays, respectively. DNA damage was assessed using the comet assay. Expression of antioxidative genes was evaluated by real-time RT-PCR analysis. Nuclear expression of CPD, phospho-p53, and Nrf2 as well as its target proteins including HO-1, CAT, and MnSOD, were assayed by immunofluorescence and western blotting. Treatment of cells with the above compounds at concentrations of 1 or 100 nM showed a dose-dependent reduction in oxidant formation. At 100 nM they inhibited the proliferation of cultured keratinocytes. When keratinocytes were irradiated with 50–200 mJ/cm 2 of UVB they also protected against DNA damage, and/or induced DNA repair by enhancing the repair of 6-4PP and attenuating CPD levels and the tail moment of comets. Treatment with test compounds increased expression of Nrf2-target genes involved in the antioxidant response including GR, HO-1, CAT, SOD1, and SOD2, with increased protein expression for HO-1, CAT, and MnSOD. The treatment also stimulated the phosphorylation of p53 at Ser-15, increased its concentration in the nucleus and enhanced Nrf2 translocation into the nucleus. In conclusion, pretreatment of keratinocytes with 1,25(OH) 2 D 3 or CYP11A1-derived vitamin D 3 - or lumisterol hydroxy-derivatives, protected them against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by the induction of the DNA repair system. Thus, the new vitamin D 3 and lumisterol hydroxy-derivatives represent promising anti-photodamaging agents.
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    SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation
    (2018-01-01) Katie D. White; Riichiro Abe; Michael Ardern-Jones; Thomas Beachkofsky; Charles Bouchard; Bruce Carleton; James Chodosh; Ricardo Cibotti; Robert Davis; Joshua C. Denny; Roni P. Dodiuk-Gad; Elizabeth N. Ergen; Jennifer L. Goldman; James H. Holmes; Shuen Iu Hung; Mario E. Lacouture; Rannakoe J. Lehloenya; Simon Mallal; Teri A. Manolio; Robert G. Micheletti; Caroline M. Mitchell; Maja Mockenhaupt; David A. Ostrov; Rebecca Pavlos; Munir Pirmohamed; Elena Pope; Alec Redwood; Misha Rosenbach; Michael D. Rosenblum; Jean Claude Roujeau; Arturo P. Saavedra; Hajirah N. Saeed; Jeffery P. Struewing; Hirohiko Sueki; Chonlaphat Sukasem; Cynthia Sung; Jason A. Trubiano; Jessica Weintraub; Lisa M. Wheatley; Kristina B. Williams; Brandon Worley; Wen Hung Chung; Neil H. Shear; Elizabeth J. Phillips; Duke-NUS Medical School Singapore; National Yang-Ming University Taiwan; Chang Gung Memorial Hospital; Wake Forest University School of Medicine; Health Sciences Authority, Government of Singapore; Vanderbilt University Medical Center; Hospital for Sick Children University of Toronto; Massachusetts General Hospital; University of Ottawa, Canada; Showa University School of Medicine; Niigata University School of Medicine; The University of Alabama at Birmingham; University of Melbourne; Wake Forest University Baptist Medical Center; Universität Freiburg im Breisgau; University of Southampton; Universite Paris 12 Val de Marne; University of California, San Francisco; Technion - Israel Institute of Technology; University of Liverpool; Murdoch University; Children's Mercy Hospitals and Clinics; National Institute of Allergy and Infectious Diseases; Loyola University Medical Center; University of Toronto; Faculty of Medicine, Ramathibodi Hospital, Mahidol University; University of Florida; National Human Genome Research Institute; The University of British Columbia; Food and Drug Administration; Memorial Sloan-Kettering Cancer Center; BC Children's Hospital; Uniformed Services University of the Health Sciences; University of Pennsylvania; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Austin Health; Groote Schuur Hospital; Harvard Medical School; University of Tennessee Health Science Center; Lackland Air Force Base
    © 2017 American Academy of Allergy, Asthma & Immunology Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.