39 results on '"Tomas Norman Dam"'
Search Results
2. Outcomes Following a Mandatory Nonmedical Switch From Adalimumab Originator to Adalimumab Biosimilars in Patients With Psoriasis
- Author
-
Nikolai Dyrberg Loft, Kawa Khaled Ajgeiy, Lone Skov, Mads Kirchheiner Rasmussen, Lars Erik Bryld, Lars Iversen, Tomas Norman Dam, Alexander Egeberg, and Christoffer Valdemar Nissen
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Dermatology ,Cohort Studies ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Psoriasis ,Internal medicine ,medicine ,Adalimumab ,Humans ,Adverse effect ,skin and connective tissue diseases ,Biosimilar Pharmaceuticals ,Original Investigation ,business.industry ,Hazard ratio ,Biosimilar ,Middle Aged ,medicine.disease ,humanities ,Clinical trial ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cohort ,business ,Cohort study ,medicine.drug - Abstract
Importance: The efficacy of adalimumab biosimilars is similar to that of brand-name adalimumab (Humira, hereinafter originator) in clinical trials. However, limited knowledge about real-world data exists for adalimumab biosimilars.Objective: To assess the outcomes following a mandatory nonmedical switch from adalimumab originator to adalimumab biosimilars in patients with psoriasis.Design, Setting, and Participants: This cohort study assesses the outcomes following a switch from adalimumab originator to an adalimumab biosimilar. Patients in the Biological Treatment in Danish Dermatology (DERMBIO) registry, a Danish nationwide registry of all patients treated with biologics (including biosimilars) for psoriasis since 2007, were assessed for eligibility. All patients who switched from adalimumab originator to an adalimumab biosimilar between November 1, 2018, and May 1, 2019, were included in the adalimumab biosimilar cohort. All patients with a visit between May 1, 2017, and November 1, 2017, treated with adalimumab originator were included in the adalimumab originator cohort. Data were analyzed from June 1, 2020, to October 10, 2021.Exposure: Switch from adalimumab originator to an adalimumab biosimilar.Main Outcomes and Measures: The primary outcome was 1-year drug retention in patients switching to adalimumab biosimilars compared with patients treated with adalimumab originator. Crude and adjusted retention rates for the adalimumab biosimilar cohort were compared with the adalimumab originator cohort with Cox proportional hazards regression using robust variance.Results: A total of 348 patients were included in the adalimumab biosimilar cohort (mean [SD] age, 52.2 [13.6] years; 251 [72.1%] male) and 378 patients in the adalimumab originator cohort (mean [SD] age, 51.1 [14.1] years; 272 [72.0%] male). The 1-year drug retention rates were 92.0% (95% CI, 89.0%-94.9%) for the adalimumab biosimilar cohort and 92.1% (95% CI, 89.4%-94.8%) for the adalimumab originator cohort. Similar hazard ratios were observed between the 2 cohorts. The crude hazard ratios were 1.02 (95% CI, 0.61-1.70; P = .94) for all causes of drug discontinuation, 0.82 (95% CI, 0.39-1.73; P = .60) for insufficient effect, and 1.41 (95% CI, 0.52-3.77; P = .50) for adverse events for the adalimumab biosimilar cohort when compared with the adalimumab originator cohort.Conclusions and Relevance: In this cohort study from Denmark, a nonmedical switch from adalimumab originator to adalimumab biosimilars was not associated with drug retention.
- Published
- 2021
3. Patient-reported Outcomes During Treatment in Patients with Moderate-to-severe Psoriasis: A Danish Nationwide Study
- Author
-
Nikolai Dyrberg Loft, Lars Erik Bryld, Alexander Egeberg, Robert Gniadecki, Lone Skov, Mads Kirchheiner Rasmussen, Tomas Norman Dam, and Lars Iversen
- Subjects
Male ,Denmark ,Severity of Illness Index ,030207 dermatology & venereal diseases ,Psoriasis Area and Severity Index ,0302 clinical medicine ,Quality of life ,Registries ,Age Factors ,General Medicine ,Dermatology Life Quality Index ,psoriasis ,Middle Aged ,humanities ,Thalidomide ,Treatment Outcome ,patient-reported outcomes ,RL1-803 ,Cohort ,medicine.drug ,Adult ,medicine.medical_specialty ,Dermatology ,Risk Assessment ,Drug Administration Schedule ,Statistics, Nonparametric ,03 medical and health sciences ,Sex Factors ,Psoriasis ,medicine ,Humans ,biologics ,Patient Reported Outcome Measures ,Rank correlation ,030203 arthritis & rheumatology ,Biological Products ,Dose-Response Relationship, Drug ,business.industry ,Arthritis, Psoriatic ,Life Quality Index ,dermatology life quality index ,medicine.disease ,Quality of Life ,Apremilast ,sense organs ,psoriasis area and severity index ,business - Abstract
The initiation and evaluation of treatment with biologics for psoriasis is based on the Psoriasis Area Severity Index (PASI) and/or Dermatological Life Quality Index (DLQI). However, these indices do not always correlate well, and changes in the DLQI do not always follow changes in the PASI. Based on data from the Danish national registry (DERMBIO), this study investigated the correlation between changes in PASI and DLQI in a cohort of patients with moderate-to-severe psoriasis treated with biologics or apremilast using Spearman’s rank correlation analyses. The correlation analysis of 1,677 patients, of whom 276 had available data after 5 years, showed weak-to-moderate correlation between PASI and DLQI during a 5-year period and between changes in PASI and DLQI: 0.58 (p
- Published
- 2019
4. Predictors of Response to Biologics in Patients with Moderate-to-severe Psoriasis: A Danish Nationwide Cohort Study
- Author
-
Alexander Egeberg, Lone Skov, Nikolai Dyrberg Loft, Christoffer V Nissen, Mads Kirchheiner Rasmussen, Christopher Willy Schwarz, Kawa Khaled Ajgeiy, and Tomas Norman Dam
- Subjects
lifestyle ,medicine.medical_specialty ,Denmark ,Dermatology ,smoking ,Etanercept ,Cohort Studies ,Psoriasis Area and Severity Index ,Psoriasis ,Internal medicine ,Ustekinumab ,Adalimumab ,Humans ,Medicine ,biologics ,Biological Products ,business.industry ,General Medicine ,Odds ratio ,medicine.disease ,Infliximab ,Treatment Outcome ,RL1-803 ,Secukinumab ,business ,bodyweight ,medicine.drug - Abstract
Identifying patient characteristics associated withachieving treatment response to biologics in patients with psoriasis could prevent expensive switching between biologics. The aim of this study was to identifypatient characteristics that predict the efficacy of treatment for biologics that inhibit tumour necrosis factor-α, interleukin-12/-23, and -17A. The study investigated biologic-naïve patients from the DERMBIO registry treated with adalimumab, etanercept, infliximab, secukinumab, or ustekinumab. Multivariable logistic models were conducted to assess associations between patient characteristics and treatment response. A total of 2,384 patients were included (adalimumab n = 911; etanercept n = 327; infliximab n = 152; secukinumab n = 323; ustekinumab n = 671). Smoking (odds ratio 0.74; 95% confidence interval (CI) 0.56–0.97; p = 0.03) and higher bodyweight (odds ratio 0.989; 95% CI 0.984–0.994; p
- Published
- 2021
5. Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis
- Author
-
Niels Møller Andersen, Vibeke Andersen, Lone Skov, Antje Bergmann, Robert Gniadecki, Ram Benny Dessau, Nikolai Dyrberg Loft, Ivan Brandslund, Hans Jürgen Hoffmann, Steffen Bank, Paal Skytt Andersen, Ulla Vogel, Tomas Norman Dam, Malene Rohr Andersen, and Lars Iversen
- Subjects
0301 basic medicine ,Oncology ,Male ,Candidate gene ,PROMOTER ,PREDICTION ,Denmark ,Interleukin-1beta ,Etanercept ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Pharmacogenetics/methods ,Receptors, Interleukin-1/genetics ,Membrane Glycoproteins ,ANTI-TNF-ALPHA ,Middle Aged ,Ustekinumab/administration & dosage ,ALLELE ,Treatment Outcome ,Molecular Medicine ,Female ,Ustekinumab ,Interleukin-1beta/genetics ,medicine.drug ,Adult ,medicine.medical_specialty ,USTEKINUMAB ,Lymphocyte Antigen 96 ,GENE POLYMORPHISMS ,Polymorphism, Single Nucleotide ,Toll-Like Receptor 2/genetics ,03 medical and health sciences ,Psoriatic arthritis ,VARIANTS AFFECT ,Internal medicine ,Psoriasis ,Psoriasis/drug therapy ,Genetics ,medicine ,Adalimumab ,Humans ,Etanercept/administration & dosage ,TOLL-LIKE RECEPTORS ,Pharmacology ,Toll-Like Receptor 9/genetics ,INTERFERON-GAMMA ,business.industry ,Tumor Necrosis Factor-alpha/antagonists & inhibitors ,Tumor Necrosis Factor-alpha ,CLINICAL-RESPONSE ,Receptors, Interleukin-1 ,Adalimumab/administration & dosage ,Membrane Glycoproteins/genetics ,medicine.disease ,Infliximab ,Toll-Like Receptor 2 ,030104 developmental biology ,Pharmacogenetics ,Toll-Like Receptor 9 ,Immunology ,business ,Infliximab/administration & dosage ,Lymphocyte Antigen 96/genetics - Abstract
Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q
- Published
- 2018
6. Safety, efficacy and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis
- Author
-
L.E. Bryld, Alexander Egeberg, Robert Gniadecki, M B Ottosen, Tomas Norman Dam, Sigurd Broesby-Olsen, Lone Skov, and Mads Kirchheiner Rasmussen
- Subjects
musculoskeletal diseases ,Male ,medicine.medical_specialty ,Denmark ,Biological Factors/therapeutic use ,Dermatology ,Kaplan-Meier Estimate ,Etanercept ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Biological Factors ,0302 clinical medicine ,Drug Stability ,Psoriasis ,Internal medicine ,Ustekinumab ,Psoriasis/drug therapy ,medicine ,Adalimumab ,Humans ,Registries ,Dermatologic Agents/therapeutic use ,Biosimilar Pharmaceuticals ,business.industry ,Biosimilar ,Middle Aged ,medicine.disease ,Infliximab ,Discontinuation ,Biosimilar Pharmaceuticals/therapeutic use ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Secukinumab ,Female ,Dermatologic Agents ,business ,medicine.drug - Abstract
Background Real-life data on newer biologic and biosimilar agents for moderate-to-severe psoriasis are lacking. Objectives To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima). Methods The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between January 1st, 2007 and March 31st, 2017. We used Kaplan-Meier survival curves and Cox-regression to examine drug survival patterns. Results A total of 3495 treatment series (2161 patients) were included (adalimumab n=1332, etanercept n=579, infliximab n=333, ustekinumab n=1055, and secukinumab n=196). Secukinumab had the highest number of PASI100 respondants, but also the lowest drug survival among all biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher-than-approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab and showed an increased (albeit low) incidence of cardiovascular events compared with the other agents. Conclusions Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, albeit that most patients on secukinumab were non-naive. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis. This article is protected by copyright. All rights reserved.
- Published
- 2017
7. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study
- Author
-
Lars Iversen, Christian Torp-Pedersen, Søren Lund Kristensen, Peter Riis Hansen, Stine Lasthein, Ole Ahlehoff, Tomas Norman Dam, Lone Skov, Jesper Lindhardsen, Robert Gniadecki, and Gunnar Gislason
- Subjects
Male ,medicine.medical_specialty ,Denmark ,Anti-Inflammatory Agents ,Severity of Illness Index ,Cohort Studies ,Risk Factors ,Psoriasis ,Internal medicine ,Severity of illness ,Confidence Intervals ,Internal Medicine ,Humans ,Medicine ,Longitudinal Studies ,Stroke ,Retrospective Studies ,business.industry ,Hazard ratio ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Surgery ,Methotrexate ,Cardiovascular Diseases ,Cohort ,Female ,Dermatologic Agents ,business ,Cohort study ,medicine.drug - Abstract
Objectives Psoriasis is a chronic inflammatory disorder associated with cardiovascular morbidity and mortality. Systemic anti-inflammatory drugs, including biological agents, are widely used in the treatment of patients with moderate to severe psoriasis and may attenuate the risk of cardiovascular disease events. We therefore examined the rate of cardiovascular disease events in patients with severe psoriasis treated with systemic anti-inflammatory drugs. Design, setting and participants Individual-level linkage of nationwide administrative databases was used to assess the event rates associated with use of biological agents, methotrexate or other therapies, including retinoids, cyclosporine and phototherapy, in Denmark from 2007 to 2009. Main outcome measure Death, myocardial infarction and stroke. Results A total of 2400 patients with severe psoriasis, including 693 patients treated with biological agents and 799 treated with methotrexate, were identified. Incidence rates per 1000 patient-years and 95% confidence intervals (CIs) for the composite endpoint were 6.0 (95% CI 2.7–13.4), 17.3 (95% CI 12.3–24.3) and 44.5 (95% CI 34.6–57.0) for patients treated with biological agents, methotrexate and other therapies, respectively. Age- and sex-adjusted hazard ratios (HRs) were 0.28 (95% CI 0.12–0.64) and 0.65 (95% CI 0.42–1.00) for patients treated with biological agents and methotrexate, respectively, using other therapies as the reference cohort. Corresponding HRs for a secondary composite endpoint of cardiovascular death, myocardial infarction and stroke were 0.48 (95% CI 0.17–1.38) and 0.50 (95% CI 0.26–0.97). Conclusion In this nationwide study of patients with severe psoriasis, systemic anti-inflammatory treatment with biological agents or methotrexate was associated with lower cardiovascular disease event rates compared to patients treated with other anti-psoriatic therapies.
- Published
- 2012
8. Topical valrubicin application reduces skin inflammation in murine models
- Author
-
E. de Darkó, Karin Stenderup, Cecilia Rosada, E. Hauge, H. Christiansen, and Tomas Norman Dam
- Subjects
integumentary system ,Anthracycline ,business.industry ,Interleukin ,Inflammation ,Dermatology ,medicine.disease ,Proinflammatory cytokine ,Psoriasis ,Immunology ,Irritant contact dermatitis ,medicine ,Skin cancer ,medicine.symptom ,business ,Valrubicin ,medicine.drug - Abstract
Summary Background Valrubicin is a cytostatic anthracycline analogue, lacking toxicity by skin and tissue contact, and represents a new drug with potential for topical treatment of psoriasis and nonmelanoma skin cancer (NMSC); the beneficial effects have been partly explained by its antiproliferative and proapoptotic characteristics. Objectives To assess the effect of valrubicin on skin inflammation as inflammation also plays a key role in psoriasis and NMSC. Methods The effect of topical valrubicin treatment on skin inflammation in vivo was addressed in skin inflammation mouse models, where 12-O-tetradecanoylphorbol 13-acetate was used to induce irritant contact dermatitis. An acute and a chronic model were included, to investigate the effect of valrubicin in short-term inflammation and in more persistent inflammation. Inflammation-associated ear oedema was evaluated by measuring ear thickness, infiltration of neutrophil cells, and expression of inflammatory cytokines, interleukin (IL)-1β and IL-6. Results Topical valrubicin treatment effectively reduced the inflammatory response in the acute and the chronic models. Conclusions The present data document an anti-inflammatory effect of valrubicin, and may suggest an interesting new role for valrubicin in other debilitating skin diseases in which inflammation is a significant factor.
- Published
- 2012
9. Hidradenitis suppurativa: a disease of the absent sebaceous gland? Sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with hidradenitis suppurativa
- Author
-
Kåre Kemp, Gregor B.E. Jemec, Bente Pakkenberg, Cecilia Rosada, Søren Kamp, Karin Stenderup, A M Fiehn, and Tomas Norman Dam
- Subjects
Sebaceous gland ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Apocrine ,Dermatology ,Biology ,Hair follicle ,medicine.disease ,Epithelium ,medicine.anatomical_structure ,Follicular phase ,Biopsy ,Follicular lumen ,medicine ,Hidradenitis suppurativa - Abstract
Summary Background The pathogenesis of hidradenitis suppurativa (HS) is not clearly understood. The nomenclature suggests an important role for the apocrine glands but recent evidence implicates the pilosebaceous unit as a more likely candidate to play a central role in the pathogenesis. Objectives Our aim was to estimate the volume of the follicular epithelium, the follicular lumen and the sebaceous glands of patients with HS and healthy controls by means of stereology. Methods Four-millimetre punch biopsies were taken from 21 patients with HS and nine healthy controls, fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin prior to volume estimation using the Cavalieri principle. Results Sebaceous gland tissue could be visualized in only 10 of 15 suitable hair follicle biopsies from patients with HS but was present in all biopsies from healthy controls (P = 0·05) and the mean sebaceous gland volume per follicle was one-seventh of that of healthy controls (P = 0·03). There was no significant difference between patients with HS and healthy controls with regard to follicular epithelium and follicle lumen volume. Conclusions Our results suggest that the absence or reduced volume of the sebaceous gland may play a role in the pathogenesis of HS. The presence of fibrosis suggests that sebaceous glands are obliterated early in the pathogenesis of HS.
- Published
- 2011
10. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris
- Author
-
Knud Kragballe, Lone Skov, Robert Gniadecki, and Tomas Norman Dam
- Subjects
musculoskeletal diseases ,Drug ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Hazard ratio ,Dermatology ,medicine.disease ,Confidence interval ,Infliximab ,Etanercept ,Internal medicine ,Psoriasis ,medicine ,Adalimumab ,skin and connective tissue diseases ,Adverse effect ,business ,media_common ,medicine.drug - Abstract
Summary Background Adherence to treatment is an indicator of treatment success. Long-term data on adherence to biologic treatment in psoriasis are lacking. Objectives To compare the tumour necrosis factor (TNF)-α inhibitors regarding drug survival rate and safety in patients with psoriasis. Methods This study is based on data from the Danish nationwide database DERMBIO covering patients with psoriasis treated with a biologic agent. All patients who received anti-TNF-α treatment in academic referral centres were included. Baseline data, adverse events, time on treatment and reason for stopping treatment were recorded. Hazard ratios (HRs) for factors determining drug survival were calculated by logistic regression. Results In total, 882 treatment series with etanercept (n = 311), adalimumab (n = 427) or infliximab (n = 144) were administered to 747 patients. Significant predictors of drug survival were: sex, the anti-TNF-α agent and the previous response to an anti-TNF-α agent. In the group of anti-TNF-α-naive patients the longest drug survival was observed for infliximab, followed by adalimumab [HR vs. infliximab 3·70, 95% confidence interval (CI) 1·99–6·89] and etanercept (HR vs. infliximab 3·18, 95% CI 1·72–5·86). The 4-year drug survival is in the range of 40% for etanercept or adalimumab vs. 70% for infliximab. There was no difference in number of adverse events. Conclusions The overall efficacy of anti-TNF-α drugs diminishes with time, as envisaged by the progressive loss of patient adherence to treatment. The major reasons for stopping treatment were loss of efficacy, followed by adverse events. Infliximab had the best patient retention ability, with 70% of patients still being on the drug after 4 years of treatment.
- Published
- 2011
11. Statistical evaluation and experimental design of a psoriasis xenograft transplantation model treated with cyclosporin A
- Author
-
Lene Alifrangis, Cecilia Rosada, Søren Andersen, Karin Stenderup, and Tomas Norman Dam
- Subjects
Oncology ,Protocol (science) ,medicine.medical_specialty ,business.industry ,Statistical model ,Dermatology ,Ciclosporin ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Internal medicine ,Cyclosporin a ,Psoriasis ,medicine ,Potency ,Analysis of variance ,business ,Molecular Biology ,medicine.drug - Abstract
Psoriasis xenograft transplantation models where human skin is transplanted onto immune-deficient mice are generally accepted in psoriasis research. Over the last decade, they have been widely employed to screen for new therapeutics with a potential anti-psoriatic effect. However, experimental designs differ in several parameters. Especially, the number of donors and grafts per experimental design varies greatly; numbers that are directly related to the probability of detecting statistically significant drug effects. In this study, we performed a statistical evaluation of the effect of cyclosporine A, a recognized anti-psoriatic drug, to generate a statistical model employable to simulate different scenarios of experimental designs and to calculate the associated statistical study power, defined as the probability of detecting a statistically significant anti-psoriatic drug treatment effect. Results showed that to achieve a study power of 0.8, at least 20 grafts per treatment group and a minimum of five donors should be included in the chosen experimental setting. To our knowledge, this is the first time that study power calculations have been performed to evaluate treatment effects in a psoriasis xenograft transplantation model. This study was based on a defined experimental protocol, thus other parameters such as drug potency, treatment protocol, mouse strain and graft size should, also, be taken into account when designing an experiment. We propose that the results obtained in this study may lend a more quantitative support to the validity of results obtained when exploring new potential anti-psoriatic drug effects.
- Published
- 2011
12. Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis
- Author
-
Ann Christina Bergmann, Hans Jürgen Hoffmann, Vibeke Andersen, Lone Skov, Mads Kirchheiner Rasmussen, Mikkel Kramme Abildtoft, Paal Skytt Andersen, Ram Benny Dessau, Niels Møller Andersen, Malene Rohr Andersen, Merete Lund Hetland, Robert Gniadecki, B. Glintborg, Tomas Norman Dam, Nikolai Dyrberg Loft, Ivan Brandslund, Steffen Bank, and Ulla Vogel
- Subjects
FACTOR-ALPHA GENE ,0301 basic medicine ,Oncology ,European People ,Candidate gene ,Heredity ,IL12B ,Physiology ,Denmark ,NF-KAPPA-B ,lcsh:Medicine ,Arthritis ,Geographical locations ,0302 clinical medicine ,IL23R GENES ,Polymorphism (computer science) ,Immune Physiology ,Medicine and Health Sciences ,Ethnicities ,Medicine ,lcsh:Science ,Innate Immune System ,Multidisciplinary ,Europe ,Genetic Mapping ,NSAID USE ,Cohort ,Cytokines ,Research Article ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Psoriatic Arthritis ,Immunology ,EARLY-ONSET ,Variant Genotypes ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,PROMOTER POLYMORPHISM ,Autoimmune Diseases ,03 medical and health sciences ,Psoriatic arthritis ,Rheumatology ,Internal medicine ,Psoriasis ,Journal Article ,Genetics ,BREAST-CANCER ,Humans ,Genetic Predisposition to Disease ,European Union ,Allele ,Alleles ,RISK LOCUS ,Danish People ,030203 arthritis & rheumatology ,business.industry ,Arthritis, Psoriatic ,lcsh:R ,Biology and Life Sciences ,Human Genetics ,Molecular Development ,medicine.disease ,030104 developmental biology ,Genetic Loci ,Immune System ,Clinical Immunology ,Population Groupings ,lcsh:Q ,Clinical Medicine ,People and places ,business ,Developmental Biology - Abstract
BACKGROUND: Psoriasis (PsO) is a chronic inflammatory disease with predominantly cutaneous manifestations. Approximately one third of patients with PsO develop psoriatic arthritis (PsA), whereas the remaining proportion of patients has isolated cutaneous psoriasis (PsC). These two phenotypes share common immunology, but with different heredity that might in part be explained by genetic variables.METHODS: Using a candidate gene approach, we studied 53 single nucleotide polymorphisms (SNPs) in 37 genes that regulate inflammation. In total, we assessed 480 patients with PsO from DERMBIO, of whom 151 had PsC for 10 years or more (PsC10), 459 patients with PsA from DANBIO, and 795 healthy controls. Using logistic regression analysis, crude and adjusted for age and gender, we assessed associations between genetic variants and PsO, PsC10, and PsA, as well as associations between genetic variants and development of PsA in PsO.RESULTS: Eleven polymorphisms in 10 genes were nominally associated with PsO and/or PsC and/or PsA (P < 0.05). After correction for multiple testing with a false discovery rate of 5%, two SNPs remained significant: TNF (rs361525) was associated with PsO, PsC10, and PsA; and IL12B (rs6887695) was associated with PsO.CONCLUSION: Among a cohort of Danish patients with moderate-to-severe psoriasis, two SNPs in the IL12B and TNF genes were associated with susceptibility of psoriasis. None of the SNPs were specifically associated with isolated cutaneous psoriasis or psoriatic arthritis.
- Published
- 2018
13. Amelioration of Psoriasis by Anti-TNF-α RNAi in the Xenograft Transplantation Model
- Author
-
Maria Jakobsen, Jacob Giehm Mikkelsen, Brian Moldt, Søren Kamp, Karin Stenderup, Tomas Norman Dam, Cecilia Rosada, and Thomas G. Jensen
- Subjects
Small RNA ,Genetic Vectors ,Transplantation, Heterologous ,Human skin ,Mice, SCID ,Gene delivery ,Biology ,Polymerase Chain Reaction ,Cell Line ,Small hairpin RNA ,Mice ,RNA interference ,Psoriasis ,Drug Discovery ,medicine ,Genetics ,Animals ,Humans ,Molecular Biology ,Pharmacology ,integumentary system ,Tumor Necrosis Factor-alpha ,Lentivirus ,RNA ,Original Articles ,medicine.disease ,Disease Models, Animal ,Immunology ,Cancer research ,Molecular Medicine ,Tumor necrosis factor alpha ,RNA Interference - Abstract
Udgivelsesdato: 2009-Jun-30 Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference (RNAi) are therapeutically relevant. To test this hypothesis the present study describes first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs) targeting human TNF-alpha mRNA and, next, the transfer of the most potent TNF-alpha shRNA variant, as assessed in vitro, to human skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-alpha shRNA treatment leads to amelioration of the psoriasis phentotype in the model, as documented by reduced epidermal thickness, normalization of the skin morphology, and reduced levels of TNF-alpha mRNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha mRNA as a target molecule for a potential persistent RNA-based treatment of psoriasis and establish the use of small RNA effectors as a novel platform for target validation in psoriasis and other skin disorders.Molecular Therapy (2009); doi:10.1038/mt.2009.141.
- Published
- 2009
- Full Text
- View/download PDF
14. AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use-improves psoriasis in a human xenograft transplantation model
- Author
-
Paul Heffner Slagle, Kenneth H. Grabstein, Tomas Norman Dam, Kurt D. Shanebeck, Cecilia Rosada, Jeffrey A. Johnson, Aijun Wang, Kenneth Christopher Thornton, Michael Van Brunt, Hengyu Xu, Gary Li, Natalie Winblade Nairn, Gordon King, Karin Stenderup, William Brady, and Marcello Marelli
- Subjects
Drug ,medicine.drug_class ,media_common.quotation_subject ,Transplantation, Heterologous ,Bioengineering ,Pharmacology ,Monoclonal antibody ,Interleukin-23 ,Biochemistry ,Mice ,Antibody Specificity ,Psoriasis ,Antibodies, Bispecific ,medicine ,Interleukin 23 ,Animals ,Humans ,Molecular Targeted Therapy ,Interleukin 6 ,Molecular Biology ,media_common ,biology ,Interleukin-6 ,Interleukin ,medicine.disease ,Rats ,Disease Models, Animal ,Targeted drug delivery ,biology.protein ,Female ,Antibody ,Biotechnology - Abstract
Targeting more than one molecule in multifactorial diseases involving several disease mediators may provide improved therapeutic efficacy. Psoriasis is a multifactorial disease in which interleukin (IL)-6 and IL-23 are important disease mediators because they facilitate development of Th17 cells; widely accepted to be associated with psoriasis. To meet the need for new therapeutics, we aimed to create a clinically relevant bispecific drug, by combining the inhibitory properties of anti-IL-6 and anti-IL-23 antibodies, exhibiting high affinity, high stability and the ability to be produced in high yield. The bispecific molecule AZ17 was created by combining high affinity binding domains originating from monoclonal antibodies targeting human IL-6 and IL-23. To allow for high and efficient production, AZ17 was assembled by site-specific bioconjugation from two individual single chain fragment variables that were synthesized separately in Escherichia coli. To improve stability and extend pharmacokinetics, a flexible poly-ethylene glycol molecule was used as linker. In preclinical psoriasis models, AZ17 reduced IL-23-induced ear inflammation and improved psoriasis in a xenograft transplantation model where psoriasis skin is transplanted onto immune-deficient mice. The data presented here suggest AZ17 to be a promising drug candidate in psoriasis and other inflammatory diseases associated with Th17 cell development.
- Published
- 2015
15. Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model
- Author
-
Grégoire Vuagniaux, Cecilia Rosada, Karin Stenderup, Tomas Norman Dam, and Bruno Gavillet
- Subjects
Adult ,medicine.medical_specialty ,Time Factors ,Epidermal thickness ,Administration, Oral ,Dermatology ,Mice, SCID ,Hsp90 inhibitor ,Psoriasis ,medicine ,Animals ,Humans ,Benzodioxoles ,HSP90 Heat-Shock Proteins ,Aged ,Skin ,Xenograft Transplantation ,business.industry ,Remission Induction ,Complete remission ,Imidazoles ,General Medicine ,Skin Transplantation ,Middle Aged ,medicine.disease ,Clinical trial ,Disease Models, Animal ,Heterografts ,Female ,Dermatologic Agents ,business ,Psoriasis treatment ,Signalling pathways ,Signal Transduction - Abstract
Debio 0932 is a novel oral heat shock protein 90 (Hsp90) inhibitor developed for anti-cancer therapy. Surprising-ly, during the first clinical trial, one psoriasis patient experienced complete remission of his skin manifestation. However, a possible therapeutic utility of Hsp90 in psoriasis has not previously been reported. The objective of the present study was to explore the ability of Debio 0932 to alleviate psoriasis in a preclinical model. A psoriasis xenograft transplantation model was employed where skin from 5 psoriasis patients was transplanted onto immunodeficient mice (8 xenografts per donor). Debio 0932 was administered perorally daily for 3 weeks and resulted in significant clinical alleviation of psoriasis by day 11 and reduced epidermal thickness evaluated post-treatment. Alleviation of psoriasis in the psoriasis xenograft transplantation model, which may be due to Hsp90's involvement in signalling pathways that are up-regulated in psoriasis, substantiates a potential role of Debio 0932 in psoriasis treatment.
- Published
- 2014
16. CANINE MODEL OF INFERTILITY AFTER SPINAL CORD INJURY
- Author
-
Mathew Putzi, Maria C. Zaborniak, Jens Sønksen, Stephen M. Papadopoulos, Dana A. Ohl, Gary Wedemeyer, Tomas Norman Dam, and Alan C. Menge
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Time Factors ,Urology ,Semen analysis ,Electroejaculation ,Male infertility ,Central nervous system disease ,Semen quality ,Dogs ,medicine ,Animals ,Spermatogenesis ,Spinal cord injury ,Sperm motility ,Infertility, Male ,Spinal Cord Injuries ,medicine.diagnostic_test ,Sperm Count ,urogenital system ,business.industry ,medicine.disease ,Spinal cord ,Surgery ,Disease Models, Animal ,medicine.anatomical_structure ,Anesthesia ,Sperm Motility ,business - Abstract
We established a canine model of subfertility after spinal cord injury and examined the time course of acute changes in semen quality and spermatogenesis after spinal cord injury.Seven dogs underwent surgical T7 spinal cord injury. Six dogs were used as controls. Electroejaculation and testicular fine needle aspiration were performed at baseline and twice weekly for 3 weeks after spinal cord injury. Semen quality change was examined by standard semen analysis. Spermatogenesis was assessed by flow cytometry of testicular fine needle aspiration in all dogs as well as by testicular histology at study conclusion in 4 controls and 4 spinal cord injured dogs.No significant changes in spinal cord injured dogs were noted before 3 weeks after injury. From baseline to 3 weeks after injury certain changes were evident in spinal cord injured dogs. Mean antegrade sperm motility decreased from 62.9% to 20.1% (p = 0.008), mean total sperm (antegrade plus retrograde total sperm) decreased from 423 to 294 x 106 which was not statistically significant, and the incidence of testicular haploid cells decreased from 75.6% to 48.3% (p = 0.028). No significant change in any parameter was present in control dogs. The mean number of mature spermatids per cross-sectional tubule on final testicular histology was significantly decreased in spinal cord injured dogs compared with controls (13.6 versus 43.9, p = 0.02).In the canine model tested the dogs readily survived spinal cord injury, electroejaculation was effective for obtaining ejaculate and fine needle aspiration allowed serial examination of spermatogenesis. Three weeks after spinal cord injury but not before 3 weeks sperm motility and spermatogenesis were significantly decreased. However, at the same point this decrease in spermatogenesis was not yet reflected in the total ejaculated sperm count.
- Published
- 2001
17. Valrubicin activates PKCa in keratinocytes: a conceivable mode of action in treating hyper-proliferative skin diseases
- Author
-
Ina Groenkjaer, Laugesen, Eva, Hauge, Stine Maria, Andersen, Karin, Stenderup, Elisabeth, de Darkó, Tomas Norman, Dam, and Cecilia, Rosada
- Subjects
Keratinocytes ,Protein Kinase C-alpha ,MAP Kinase Signaling System ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Antineoplastic Agents ,Cell Differentiation ,Lipid Metabolism ,Skin Diseases ,Cell Line ,Protein Transport ,Doxorubicin ,Humans ,Phosphorylation ,Myristoylated Alanine-Rich C Kinase Substrate ,Cell Proliferation - Abstract
Valrubicin is a semisynthetic anthracycline developed as an anti-cancer drug able to ameliorate psoriasis and non-melanoma skin cancer (NMSC) by topical application in animal models. Valrubicin decreases cell proliferation, and induces apoptosis; however its mode of action is still unknown. Valrubicin localizes in the cytoplasm and its valerate moiety resembles diacylglycerol, an activator of protein kinase C (PKC) α, which belongs to the PKC family of cytoplasmic serine/threonine protein kinases. PKCα is observed in the suprabasal layers of normal skin and is associated to keratinocyte growth arrest and differentiation processes. In hyper-proliferative skin diseases the presence of PKCα is altered.The aim of the present study was to investigate valrubicin's mode of action in keratinocytes by studying its possible effect on PKCα activation.PKCα's characteristic to translocate from the cytoplasm to the cellular membrane when activated was assessed by measuring the amount of PKCα in the soluble and membrane-bound protein fractions isolated from valrubicin stimulated keratinocytes and by visualizing PKCα in stimulated cells over time. Downstream signaling was investigated by measuring the amount of phosphorylated Myristoylated Alanine-rich C-kinase substrate (MARCKS) and extracellular signal-regulated kinases (ERK) 1/2 of valrubicin-stimulated keratinocytes. To investigate whether there was a direct interaction between valrubicin and PKCα, an activity assay employing purified PKCα protein was used.Valrubicin activates PKCα in vitro as shown by PKCα's translocation and phosphorylation of downstream signaling molecules.Valrubicin stimulates PKCα activity and downstream signaling which may contribute to its beneficial effect in psoriasis and NMSC.
- Published
- 2013
18. Statistical evaluation and experimental design of a psoriasis xenograft transplantation model treated with cyclosporin A
- Author
-
Karin, Stenderup, Cecilia, Rosada, Lene, Alifrangis, Søren, Andersen, and Tomas Norman, Dam
- Subjects
Adult ,Analysis of Variance ,Transplantation, Heterologous ,Mice, SCID ,Skin Transplantation ,Middle Aged ,Disease Models, Animal ,Mice ,Treatment Outcome ,Research Design ,Data Interpretation, Statistical ,Cyclosporine ,Animals ,Humans ,Psoriasis ,Computer Simulation ,Aged - Abstract
Psoriasis xenograft transplantation models where human skin is transplanted onto immune-deficient mice are generally accepted in psoriasis research. Over the last decade, they have been widely employed to screen for new therapeutics with a potential anti-psoriatic effect. However, experimental designs differ in several parameters. Especially, the number of donors and grafts per experimental design varies greatly; numbers that are directly related to the probability of detecting statistically significant drug effects. In this study, we performed a statistical evaluation of the effect of cyclosporine A, a recognized anti-psoriatic drug, to generate a statistical model employable to simulate different scenarios of experimental designs and to calculate the associated statistical study power, defined as the probability of detecting a statistically significant anti-psoriatic drug treatment effect. Results showed that to achieve a study power of 0.8, at least 20 grafts per treatment group and a minimum of five donors should be included in the chosen experimental setting. To our knowledge, this is the first time that study power calculations have been performed to evaluate treatment effects in a psoriasis xenograft transplantation model. This study was based on a defined experimental protocol, thus other parameters such as drug potency, treatment protocol, mouse strain and graft size should, also, be taken into account when designing an experiment. We propose that the results obtained in this study may lend a more quantitative support to the validity of results obtained when exploring new potential anti-psoriatic drug effects.
- Published
- 2011
19. Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin
- Author
-
Rasmus O. Bak, Line Petersen, Brian Moldt, Cecilia Rosada, Thomas G. Jensen, Maria Jakobsen, Frederik Dagnæs-Hansen, Søren Kamp, Karin Stenderup, Jacob Giehm Mikkelsen, and Tomas Norman Dam
- Subjects
Injections, Intradermal ,medicine.medical_treatment ,Genetic Vectors ,Transplantation, Heterologous ,Down-Regulation ,Mice, SCID ,Dermatology ,Biology ,Cell Line ,Proinflammatory cytokine ,Mice ,Psoriasis ,Ustekinumab ,lcsh:Dermatology ,medicine ,Animals ,Humans ,RNA, Messenger ,RNA, Small Interfering ,Cells, Cultured ,Interleukin-12 Subunit p40 ,Lentivirus ,Gene Transfer Techniques ,Interleukin ,RNA ,lcsh:RL1-803 ,medicine.disease ,Transplantation ,Disease Models, Animal ,HEK293 Cells ,Cytokine ,Immunology ,Tumor necrosis factor alpha ,HeLa Cells ,Plasmids ,Research Article ,medicine.drug - Abstract
Background Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The pathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine production. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical use. We have previously documented the therapeutic applicability of targeting TNFα mRNA for RNA interference-mediated down-regulation by anti-TNFα small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted psoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and IL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs. Methods Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels. Results Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimick the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination. Conclusions Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.
- Published
- 2011
20. Topical application of valrubicin has a beneficial effect on developing skin tumors
- Author
-
Karin Stenderup, Ina Groenkjaer Laugesen, Cecilia Rosada, Frederik Dagnæs-Hansen, Elisabeth de Darkó, Tomas Norman Dam, and Stine Andersen
- Subjects
Keratinocytes ,Cancer Research ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Anthracycline ,Cell Survival ,Administration, Topical ,Cell ,Human skin ,Apoptosis ,Mice ,Psoriasis ,medicine ,Animals ,Humans ,Viability assay ,Valrubicin ,Cells, Cultured ,Skin ,Bladder cancer ,Antibiotics, Antineoplastic ,integumentary system ,Papilloma ,business.industry ,Actinic keratosis ,General Medicine ,medicine.disease ,Keratosis, Actinic ,medicine.anatomical_structure ,Doxorubicin ,Cancer research ,Carcinoma, Squamous Cell ,business ,Cell Division ,medicine.drug - Abstract
Valrubicin is a second generation anthracycline characterized by an excellent safety profile presenting no skin toxicity or necrosis upon contact. In its current liquid formulation (Valstar; Indevus Pharmaceuticals, Lexington, MA), it is approved solely for the treatment of bladder cancer. Recently, valrubicin was incorporated in a cream formulation rendering this drug available for topical application. The cytostatic property of valrubicin can, thus, be employed for treating hyperproliferative skin diseases as was recently described for psoriasis. In the present study, the effect of topical application of valrubicin was investigated in skin tumor development; we hypothesized that valrubicin may be employed in treating actinic keratosis, a hyperproliferative skin condition that may transform into malignancy. A two-stage chemical mouse skin carcinogenesis model that represents the multistage etiology of human skin cancer-from developing papillomas to squamous cell carcinoma (SCC) was used. Moreover, two human skin SCC cell lines: DJM-1 and HSC-1 were cultured, to further investigate the effect of valrubicin in vitro. Cell viability was assessed by adenosine triphosphate presence, proliferation as proliferative cell nuclear antigen expression and apoptosis as cytokeratin 18 cleavage, caspase activation, poly-adenosine diphosphate-ribose-polymerase cleavage and bax and bcl-2 regulation. Valrubicin significantly inhibited tumor formation in the mouse skin carcinogenesis model and significantly decreased cell viability of the cultured human skin SCC cells. In both mouse skin and SCC cells, proliferation was significantly decreased. Apoptosis was significantly increased in SCC cells but unchanged in the treated mouse skin at study completion. This study demonstrated that topical application of valrubicin has a beneficial effect in treating developing skin tumors.
- Published
- 2010
21. Regulation of cytokine expression by lentivirus-encoded RNA antagomirs
- Author
-
Bak, Rasmus O., Line Barrett Petersen, Brian Moldt, Karin Stenderup, Cecilia Rosada Kjeldsen, Lars Aagaard, Tomas Norman Dam, and Jacob Giehm Mikkelsen
- Subjects
Lentivirale vektorer ,miRNA regulering ,Lentiviral vectors ,miRNA - Published
- 2010
22. Valrubicin in a topical formulation treats psoriasis in a xenograft transplantation model
- Author
-
Frederik Dagnæs-Hansen, Søren Kamp, Karin Stenderup, Elisabeth de Darkó, Tomas Norman Dam, and Cecilia Rosada
- Subjects
Adult ,Keratinocytes ,Pathology ,medicine.medical_specialty ,Administration, Topical ,Stratum granulosum ,Antineoplastic Agents ,Dermatology ,Mice, SCID ,Biochemistry ,Mice ,In vivo ,Psoriasis ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Proliferation Marker ,Molecular Biology ,Valrubicin ,Aged ,Cell Proliferation ,Bladder cancer ,integumentary system ,business.industry ,Cell Biology ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Urinary Bladder Neoplasms ,Apoptosis ,Doxorubicin ,Cancer research ,Epidermis ,Keratinocyte ,business ,Neoplasm Transplantation ,medicine.drug - Abstract
Valrubicin is a cytostatic drug currently approved by the American Federal Drug Administration as a trademarked Valstar sterile solution for the treatment of bladder cancer. Valrubicin has shown an excellent therapeutic potential with minimal toxicity. This study investigated the effect in vivo of treating psoriasis with a daily topical application of valrubicin cream in a psoriasis xenograft transplantation model. Psoriasis is characterized by an accelerated keratinocyte proliferation, resulting in increased epidermal thickness. We thus studied the cytostatic potential of valrubicin on epidermal keratinocytes. In vivo, valrubicin treatment resulted in a normalization of epidermal morphology and a reduction in epidermal thickness after 12 days. In addition, the dermal vessel pattern was reduced and the stratum granulosum was regained. Staining for a regenerative proliferation marker showed a decrease in keratinocyte proliferation, and scattered epidermal cells showed apoptosis. In vitro, valrubicin was shown to localize solely to the cell cytoplasm in cultured keratinocytes and to reduce keratinocyte proliferation as well as increase apoptosis by activation of caspases 3, 7, and 9. Our results indicated that valrubicin successfully treats psoriasis in a xenograft transplantation model, suggesting that topical valrubicin may become an upcoming treatment for psoriasis.
- Published
- 2009
23. Topical application of Valrubicin cream treats psoriasis
- Author
-
Cecilia Rosada Kjeldsen, Karin Stenderup, Elisabeth de Darkó, Frederik Dagnæs-Hansen, Søren Kamp, and Tomas Norman Dam
- Published
- 2009
24. Valrubicin in a new topical formulation treats skin cancer
- Author
-
Stine Maria Andersen, Cecilia Rosada Kjeldsen, Frederik Dagnæs-Hansen, Elisabeth de Darkó, Tomas Norman Dam, and Karin Stenderup
- Published
- 2009
25. Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model
- Author
-
Lars Fogh Iversen, Cecilia Rosada, Torben Steiniche, Frederik Dagnæs-Hansen, Anne Worsaae, Knud Kragballe, Karin Stenderup, H. Lindgreen Holmberg, H. Wöldike, John Rømer, S. Zahn, Tomas Norman Dam, Erik Hasselager, and Jes Thorn Clausen
- Subjects
Adult ,medicine.medical_treatment ,Transplantation, Heterologous ,Human skin ,Mice, SCID ,Dermatology ,law.invention ,Mice ,Interleukin 20 ,Antibody Specificity ,law ,Psoriasis ,Animals ,Humans ,Medicine ,Aged ,Cell Proliferation ,Xenograft Transplantation ,biology ,business.industry ,Interleukins ,Remission Induction ,Interleukin ,Skin Transplantation ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Cytokine ,Immunology ,biology.protein ,Recombinant DNA ,Antibody ,business ,Signal Transduction - Abstract
Udgivelsesdato: 2009-Feb BACKGROUND: Interleukin (IL)-20 is a recently discovered cytokine displaying increased levels in psoriatic lesions. Interestingly, IL-20 levels decrease with antipsoriatic treatment, correlating with clinical improvement. However, the role of IL-20 in the aetiology of psoriasis is unknown. OBJECTIVES: In this study, we investigate the effects both of blocking IL-20 signalling in psoriatic plaques and of adding IL-20 to nonlesional psoriasis skin. METHODS: We employed the human skin xenograft transplantation model in which psoriatic plaques and nonlesional keratome skin biopsies obtained from donors with moderate to severe plaque psoriasis were transplanted on to immuno-deficient mice. The transplanted mice were treated with anti-IL-20 antibodies or recombinant human IL-20. RESULTS: We demonstrate that blocking IL-20 signalling with anti-IL-20 antibodies induces psoriasis resolution and inhibits psoriasis induction. We also demonstrate that continuous IL-20 infusion, together with injection of additional nonactivated leucocytes, promotes induction of psoriasis in nonlesional skin from patients with psoriasis. CONCLUSIONS: The results suggest that IL-20 plays a critical role in the induction and maintenance of psoriasis, and IL-20 is suggested as a new possible specific target in psoriasis treatment.
- Published
- 2009
26. [Interleukin-20--a new target in psoriasis treatment]
- Author
-
Karin, Stenderup, Cecilia, Rosada, and Tomas Norman, Dam
- Subjects
Mice ,Gene Expression Regulation ,Interleukins ,Animals ,Humans ,Immunologic Factors ,Psoriasis ,Receptors, Interleukin ,Signal Transduction ,Skin - Abstract
Interleukin-20 (IL-20) is suggested as a new target in psoriasis treatment. It was first described in 2001, and the potential role of this cytokine in psoriasis was suggested because mice which were over-expressing IL-20 developed a psoriasis-like phenotype of the skin. Subsequently, IL-20 expression levels were found to be increased in psoriasis skin, and it was observed that these levels normalized upon psoriasis treatment. In the psoriasis xenograft transplantation model, administration of IL-20 to non-lesional psoriasis skin transplanted onto immune-deficient mice demonstrated that IL-20 was involved in the psoriasis induction. More interestingly, improvement of psoriasis was induced by blocking IL-20 signaling.
- Published
- 2008
27. Alleviation of psoriasis upon genetic knockdown of human tumour necrosis factor-alfa by lentivirus-encoded short hairpin RNA in a xenograft transplantation model
- Author
-
Karin Stenderup, Maria Vad Jakobsen, Cecilia Rosada Kjeldsen, Brian Moldt, Søren Kamp, Tomas Norman Dam, Jensen, Thomas G., and Jacob Giehm Mikkelsen
- Subjects
shRNA ,mouse model ,psoriasis ,musemodel - Published
- 2008
28. Partial Correction of Psoriasis upon Genetic Knock-Down of Human TNF-α by Lentivirus-Encoded shRNAs in a Xenograft Mouse Model
- Author
-
Maria Jakobsen, Karin Stenderup, Cecilia Rosada Kjeldsen, Brian Moldt, Søren Kamp, Tomas Norman Dam, Jensen, Thomas G., and Jacob Giehm Mikkelsen
- Subjects
shRNA ,Oligonucleotide Based Therapies ,Lentivirus VectorsRNAi - Abstract
The proinflammatory cytokine Tumor Necrosis Factor alpha (TNF-) is upregulated in inflammatory psoriatic skin. The increased level of TNF- protein is thought to cause keratinocyte hyperproliferation, leukocyte infiltration as well as growth and dilation of superficial blood vessels, which are all characteristics of human psoriasis skin. Blockade of TNF- function with specific inhibitors at the protein level has resulted in a rapid clinical improvement in psoriasis patients, demonstrating that TNF- inhibition offers a promising therapy of psoriasis. Whether TNF--encoding RNA is a valid therapeutic target, however, is still a matter of speculation, as recent findings have suggested that the level of TNF- is not increased in psoriatic skin. To test the hypothesis that TNF- in skin can be stably down-regulated by RNA interference (RNAi), we designed a panel of short hairpin RNAs (shRNAs) targeting human TNF-. Their efficiency in down-regulating TNF- protein expression was evaluated using a Renilla luciferase screening-assay based upon targeting of luc-TNF- fusion RNAs and a transient co-transfection assay. The three most potent shRNAs, which at most reduced the expression from target templates to 15% of the control samples treated with irrelevant shRNAs, were selected and cloned into lentiviral vectors. The lentiviral vectors expressing TNF- shRNAs were used to transduce HEK-293 cells and verify vector-derived knock-down of stable TNF- expression in vitro. The most efficient TNF--directed shRNA, which in cell lines reduced the amount of released TNF- more than 50% upon viral transduction, was selected for in vivo studies. In vivo studies were carried out in a xenograft mouse model in which human psoriatic plaques keratome skin biopsies were transplanted onto SCID mice. Initial studies using eGFP-encoding lentiviral vectors demonstrated efficient transduction of human psoriatic skin. Grafted psoriatic skin was exposed to viral vector-encoded TNF- shRNAs by a single intradermal injection of purified VSV-G-pseudotyped lentiviral vectors (150l containing 46.4 ng p24/l was injected at a single site). Biopsies were taken three weeks after injection. qPCR-based measurements of TNF- mRNA in skin treated with lentiviral vector-encoded TNF- shRNA demonstrated a 50% reduction in the level of TNF- mRNA. Most interestingly, the epidermal thickness of the human psoriatic plaques was reduced relative to mice treated with lentiviral vectors encoding an irrelevant shRNA. In conclusion, our results demonstrate that lentiviral vector-encoded TNF- shRNAs have the potential to down-regulate TNF- production both in vitro and in vivo. Phenotypic changes in shRNA-treated psoriatic skin suggest that TNF--encoding RNA is a valid therapeutic target in psoriasis treatment.
- Published
- 2008
29. Interleukin-20 as a target in psoriasis treatment
- Author
-
Anne Worsaae, Karin Stenderup, Tomas Norman Dam, Cecilia Rosada, and Jes Thorn Clausen
- Subjects
Angiogenesis ,General Neuroscience ,medicine.medical_treatment ,Interleukins ,Interleukin ,Human skin ,Receptors, Interleukin ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Cytokine ,Interleukin 20 ,History and Philosophy of Science ,In vivo ,Psoriasis ,Immunology ,medicine ,Animals ,Humans ,Cell Proliferation ,Signal Transduction - Abstract
Interleukin-20 (IL-20) is a new member of the IL-10 cytokine family discovered by a structural algorithm. IL-20 transgenic mice displayed skin abnormalities reminiscent of psoriasis, a finding that has prompted the investigation of this new interleukin in relation to this disease. This article reviews the role of IL-20 and its implication in psoriasis. It is shown that IL-20 and its receptors are found in human skin and that IL-20 is involved in proliferation, angiogenesis, and chemotaxis, all characteristics of psoriasis. We demonstrated that IL-20 induced the thickening of human epidermis in vivo; however, this thickening does not seem to be related to a direct effect of IL-20 on hyperproliferation since the growth of normal human epidermal keratinocytes (NHEKs) cultured in vitro was not affected by IL-20. On the other hand, in vitro, IL-20 stimulated human peripheral blood mononuclear cells (PBMCs) to produce proinflammatory cytokines and, in vivo, IL-20 in combination with PBMCs induced psoriasis. This may suggest that IL-20 indirectly exerts its proliferative effects on keratinocytes via immune cells present in the skin. Finally, we found that blocking IL-20 signaling in psoriasis improves psoriasis, suggesting that IL-20 is a potential target in psoriasis treatment.
- Published
- 2007
30. In situ depletion of CD4+ T cells in human skin by Zanolimumab
- Author
-
Frederik Dagnæs-Hansen, J.G.J. van de Winkel, Louise S. Villadsen, Lone Skov, O. Baadsgaard, J. Rygaard, Janine Schuurman, Tomas Norman Dam, and Paul W. H. I. Parren
- Subjects
CD4-Positive T-Lymphocytes ,T cell ,CD3 ,Biopsy ,Transplantation, Heterologous ,Human skin ,Antineoplastic Agents ,Dermatology ,Mice, SCID ,Antibodies, Monoclonal, Humanized ,Mice ,Psoriasis ,Medicine ,Animals ,Humans ,Skin ,biology ,business.industry ,Zanolimumab ,Antibodies, Monoclonal ,General Medicine ,T lymphocyte ,medicine.disease ,CD4 Lymphocyte Count ,Lymphoma, T-Cell, Cutaneous ,Disease Models, Animal ,medicine.anatomical_structure ,Monoclonal ,Immunology ,biology.protein ,business ,CD8 ,medicine.drug - Abstract
CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not CD8(+) CD3(+) T cells. The capacity of Zanolimumab to deplete the CD4(+) T cells in the skin may be of importance in diseases where CD4(+) T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody is currently in a phase III clinical trial for CTCL, a disease for which there is no safe and effective treatment available today.
- Published
- 2006
31. Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with nonlesional psoriatic skin
- Author
-
Claus Johansen, Tomas Norman Dam, Lars Iversen, Mads Kirchheiner Rasmussen, and Knud Kragballe
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,JUNB ,Proto-Oncogene Proteins c-jun ,Blotting, Western ,Electrophoretic Mobility Shift Assay ,Dermatology ,Biology ,chemistry.chemical_compound ,Calcitriol ,Psoriasis ,medicine ,Humans ,Electrophoretic mobility shift assay ,Northern blot ,RNA, Messenger ,Transcription factor ,Calcipotriol ,Aged ,Skin ,integumentary system ,Activator (genetics) ,Binding protein ,Middle Aged ,medicine.disease ,Blotting, Northern ,Molecular biology ,DNA-Binding Proteins ,Transcription Factor AP-1 ,chemistry ,Gene Expression Regulation ,Female ,Dermatologic Agents ,Proto-Oncogene Proteins c-fos - Abstract
Summary Background Psoriasis is a common benign skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. The transcription factor activator protein 1 (AP-1) is known to play an important role in cell proliferation and differentiation. Objectives To investigate AP-1 DNA binding activity in psoriatic skin. Methods Keratome biopsies were taken from patients with plaque-type psoriasis. Electrophoretic mobility shift assays were used to determine the AP-1 DNA binding activity, whereas Western and Northern blotting was used to determine Jun and Fos protein and mRNA expression. Results We found that AP-1 DNA binding activity was almost completely abolished in lesional psoriatic skin compared with nonlesional psoriatic skin. Furthermore, experiments revealed that the protein and mRNA expression of the AP-1 subunits c-Fos, Fra-1 and c-Jun was reduced in lesional psoriatic skin compared with nonlesional psoriatic skin, whereas the protein and mRNA expression of the subunit JunB was increased. Topical application of the vitamin D analogue calcipotriol under occlusion to involved psoriatic skin for 4 days resulted in an increase in AP-1 DNA binding activity, and an increase in the protein and mRNA expression of c-Fos, Fra-1 and c-Jun, together with a decrease in JunB protein and mRNA expression. Conclusions Together, these results suggest that the activity of the transcription factor AP-1 is impaired in lesional psoriatic skin and that this impairment may be important for the disturbed epidermal growth observed in psoriasis.
- Published
- 2004
32. 1alpha,25-dihydroxycholecalciferol and cyclosporine suppress induction and promote resolution of psoriasis in human skin grafts transplanted on to SCID mice
- Author
-
Brian J. Nickoloff, J.J. Voorhees, Sewon Kang, and Tomas Norman Dam
- Subjects
Pathology ,medicine.medical_specialty ,Transplantation, Heterologous ,CD4-CD8 Ratio ,Human skin ,vitamin D ,Dermatology ,Mice, SCID ,Biochemistry ,Mice ,Dermis ,Calcitriol ,T-Lymphocyte Subsets ,Psoriasis ,medicine ,Animals ,Humans ,IL-2 receptor ,Parakeratosis ,Molecular Biology ,superantigens ,business.industry ,Receptors, Interleukin-2 ,Cell Biology ,Skin Transplantation ,Ciclosporin ,medicine.disease ,Flow Cytometry ,Rete pegs ,Interleukin-10 ,medicine.anatomical_structure ,Immunology ,Cyclosporine ,medicine.symptom ,business ,immune deviation ,CD8 ,Immunosuppressive Agents ,medicine.drug - Abstract
Accumulating evidence has emphasized the importance of immunocompetent cells in determining the psoriatic phenotype. We have investigated the effect of 1alpha,25-dihydroxycholecalciferol, the naturally occurring active form of vitamin D3, cyclosporine A, and interleukin-10 on the phenotype of human psoriatic skin xenotransplants. First, psoriatic skin transplants were injected with either 1alpha,25-dihydroxy- cholecalciferol, cyclosporine A, or interleukin-10. Second, we determined the ability of autologous lymphocytes, activated in vitro using staphylococcal enterotoxin B and interleukin-2 and then exposed to either 1alpha, 25-dihydroxycholecalciferol or cyclosporine A, to induce psoriatic lesions if they were injected into the dermis of uninvolved skin grafts. We found that injections into transplanted psoriatic plaques of either 1alpha,25-dihydroxycholecalciferol or cyclosporine A, but not interleukin-10, resulted in a consistent reduction in the clinical and histologic score of psoriasis with remission towards uninvolved psoriatic skin. Injection of activated immunocytes into symptomless psoriatic skin grafts, changed the grafts towards plaque-type psoriasis with silvery scale, parakeratosis, elongated rete pegs, acanthosis, and dermal angiogenic reaction. In contrast, if activated immunocytes were exposed to 1alpha, 25-dihydroxycholecalciferol or cyclosporine A prior to injection, only minimal changes occurred. It was determined that neither staphylococcal enterotoxin B and interleukin-2 activation by itself, nor the drugs investigated, changed the CD4/CD8 ratio of activated (CD25 + ) cells. Our results are consistent with the hypothesis that psoriasis may be induced by activated T lymphocytes, and indicate that novel immunomodulatory drugs can serve to inhibit the pathogenetic ability of immunocytes in psoriasis.
- Published
- 1999
33. Pharmacological Undertreatment of Coronary Risk Factors in Patients with Psoriasis: Observational Study of the Danish Nationwide Registries
- Author
-
Søren Lund Kristensen, Tomas Norman Dam, Ole Ahlehoff, Stine Lasthein, Robert Gniadecki, Christian Torp-Pedersen, Gunnar Gislason, Jesper Lindhardsen, Lone Skov, Peter Riis Hansen, and Lars Iversen
- Subjects
Male ,Drugs and Devices ,medicine.medical_specialty ,Epidemiology ,Science ,Denmark ,Inflammatory Diseases ,Myocardial Infarction ,Coronary Disease ,Coronary Artery Disease ,Dermatology ,Cardiovascular ,Cardiovascular Pharmacology ,Pharmacotherapy ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Psoriasis ,medicine ,Humans ,Medical history ,Registries ,Cardiovascular Disease Epidemiology ,Multidisciplinary ,biology ,business.industry ,Pharmacoepidemiology ,Angiotensin-converting enzyme ,Middle Aged ,Angina ,Atherosclerosis ,medicine.disease ,Interventional Cardiology ,Surgery ,Concomitant ,Hypertension ,biology.protein ,Medicine ,Female ,Observational study ,business ,Dyslipidemia ,Research Article - Abstract
BACKGROUND: Patients with psoriasis have increased prevalence of coronary risk factors and limited recent results have suggested that these risk factors are undertreated in patients with psoriasis. This may contribute to the increased risk of cardiovascular diseases observed in patients with psoriasis.OBJECTIVE: To examine the pharmacological treatment of coronary risk factors in patients with severe psoriasis treated with biologic agents in a real-world setting.METHODS AND FINDINGS: Medical history of patients with severe psoriasis treated with biologic agents in the time period 2007-09 was retrieved from a Danish nationwide registry (DERMBIO). Individual-level linkage of nationwide administrative registries of hospitalizations, concomitant medications, and socioeconomic status was performed to gain insights into the use of pharmacological treatment. A total of 693 patients (mean age 46.1 ± 12.7 years, 65.7% male) with severe psoriasis treated with biologic agents were identified. Hypertension, hypercholesterolemia, and diabetes mellitus were identified in 16.6%, 9.2%, and 6.7% of cases, respectively. Patients with severe psoriasis were significantly less likely to receive cardiovascular pharmacotherapy compared to age, sex, and coronary risk factor matched controls. In psoriatic patients with hypertension 27.7% received no antihypertensive pharmacotherapy. Patients with dyslipidemia received cholesterol-lowering medications in 55.8% of cases and patients with diabetes mellitus received angiotensin converting enzyme inhibitors/angiotensin II receptor blockers and cholesterol-lowering medications in 42.1% and 23.7% of cases, respectively. Similar results were found for the subset of patients with >1 coronary risk factor and for high risk patients with established atherosclerotic disease.CONCLUSION: This nationwide study of patients with severe psoriasis demonstrated substantial undertreatment of coronary risk factors. Increased focus on identifying cardiovascular risk factors and initiation of preventive cardiovascular pharmacotherapy in patients with psoriasis is warranted.
- Published
- 2012
34. CANINE MODEL OF INFERTILITY FOLLOWING SPINAL CORD INJURY-TIMING OF SEMEN QUALITY AND TESTIS FLOW CYTOMETRY CHANGES
- Author
-
Dana A. Ohl, Tomas Norman Dam, Jens Sønksen, Maria C. Zaborniak, and Gary Wedemeyer
- Subjects
Infertility ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Urology ,medicine.disease ,Flow cytometry ,Andrology ,Semen quality ,medicine ,business ,Canine model ,Spinal cord injury - Published
- 1999
35. Targeting of human interleukin-12B by small hairpin RNAa in xenografted psoriatic skin
- Author
-
Karin Stenderup, Rasmus Otkjær Bak, Cecilia Rosada Kjeldsen, Line Berrett Petersen, Brian Moldt, Frederik Dagnæs-Hansen, Maria Jakobsen, Søren Kamp, Jensen, Thomas G., Tomas Norman Dam, and Jacob Giehm Mikkelsen
36. Interleukin 20 controls psoriasis induction and maintenance in a human xenograft mouse model
- Author
-
Cecilia Rosada Kjeldsen, Karin Stenderup, Frederik Dagnæs-Hansen, Torben Steiniche, Erik Hasselager, Iversen, Lars F., Stephan Zahn, Holmberg, Heidi L., Anne Worsaae, John Rømer, Knud Kragballe, Jes Thorn Clausen, and Tomas Norman Dam
37. Interleukin-20 plays a critical role in psoriasis
- Author
-
Karin Stenderup, Kristian Otkjær, Cecilia Rosada Kjeldsen, Frederik Dagnæs-Hansen, Torben Steiniche, Erik Hasselager, Iversen, L. F., Zahn, S., Holmberg, H. L., Anne Worsaae, Rømer, J., Knud Kragballe, Clausen, Jens T., and Tomas Norman Dam
38. Cytokine regulation in psoriasis by endogenous and viral vector-delivered small non-coding RNAs
- Author
-
Bak, Rasmus O., Maria Jakobsen, Karin Stenderup, Cecilia Rosada Kjeldsen, Line Barrett Petersen, Brian Moldt, Frederik Dagnæs-Hansen, Søren Kamp, Jensen, Thomas G., Tomas Norman Dam, and Jacob Giehm Mikkelsen
- Subjects
RNA interference ,Cytokine regulation ,Lentivirale vektorer ,Psoriasis ,Lentiviral vectors ,RNA interferens
39. Is TNF-a-targeted short hairpin RNA (shRNA) a novel potential therapeutic tool in psoriasis treatment?
- Author
-
Karin Stenderup, Maria Jakobsen, Cecilia Rosada Kjeldsen, Brian Moldt, Søren Kamp, Tomas Norman Dam, Jensen, Thomas G., and Jacob Giehm Mikkelsen
- Subjects
shRNA ,TNF-a ,psoriasis - Abstract
TNF-α is a well known target in psoriasis treatment and biological treatments targeting TNF-a are already clinically used against psoriasis and psoriasis arthritis. Attention is however given to a novel therapeutic tool: RNA interference that controls gene silencing. This study investigates the efficiency of targeting TNF-a with specific short hairpin RNA (shRNA) and explores its potential in treating psoriasis. ShRNAs targeting human TNF-α mRNA were generated. Their efficiency in down-regulating TNF-a protein expression was evaluated using a Renilla luciferase screening-assay and a transient co-transfection assay. The expression cassette encoding the most efficient TNF-a shRNA was inserted into a lentiviral vector, allowing proficient gene delivery. The lentiviral vector is integrated into the host genome and establishes life-long infection and persistent shRNA expression. The lentiviral vector expressing TNF-a shRNA was used to transduce HEK293 cells and verify vector-derived TNF-a knockdown in vitro. In vivo, psoriasis skin was exposed to lentiviral TNF-a shRNAs by a single intra-dermal injection. Psoriasis skin for the in vivo study was obtained from psoriatic plaque skin biopsies that were transplanted onto SCID mice employing the psoriasis xenograft model. Three weeks after exposure, biopsies were taken and the epidermal thickness as an endpoint for evaluating psoriasis and the levels of TNF-a mRNA were measured. The lentiviral TNF-a shRNAs down-regulated the TNF-a expression in vitro and in vivo by 50% and, most interestingly, the epidermal thickness of the psoriatic plaques was reduced. In conclusion, our results demonstrate that lentiviral TNF-a shRNAs have the potential to down-regulate TNF-a production in vitro and in vivo. The decreased epidermal thickness suggests a potential role for TNF-a shRNAs as a new therapeutic agent in psoriasis treatment.
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.