Vitiligo is an acquired skin disorder characterized by the loss of pigment cells from the epidermis. We found there were abundant SENP proteins couple with the abnormal chemokines in vitiligo lesions. SUMOylation is a reversible process that is catalyzed by the enzymes and reversed by a family of Sentrin/SUMO-specific proteases(SENPs). Interferon-g (IFN-g) triggers keratinocytes for inflammation response by activating the intracellular JAKÀSTAT1 signaling. By analyzing the expression profiles of genes from SENP1-/-cells, we found the down-regulation of IFN target genes in SENP-/-cell in comparison with SENP+/+. Therefore, we proprse that SENP1 plays an important role in IFN induce signal and chemokines activation. We found the down-regulation of IFN-induced genes in SENP1-/-or SENP1-silenced KCs, and the decrease in activation of Jak2 and Stat1. SENP1-deficient KCs show defects in IFN-g signaling and type 1 T helper cells Chemokines activation. Meanwhile, we also find that SENP1 expression is induced by IFN-g. PTP1B in SENP1-deficient KCs is highly SUMOylated, which reduces PTP1B-inducedde-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient keratinocytes. Accordingly, SENP1-deficient keratinocytes show reduced ability to resist UVB. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3SUMOylation balance in keratinocyte function.
Epidermal growth factor (EGF) is known to stimulate skin cell growth and synthesis of extracellular matrix such as hyaluronan(HA) which is decreased with aging in skin. However, EGF is hard to penetrate the stratum corneum and permeate into skin due to its size and hydrophilicity. To improve the skin delivery of EGF, we have used multi-lamellar complexes consist of EGF and 1,2-dioleoyl-3-tirmethylammonium-propane (DOTAP). EGF-DOTAP complex showed higher permeation rate in human skin and synthesis of hyaluronan in human skin equivalent model than normal liposome. A randomized, double-blind, vehiclecontrolled, split-face study was designed to evaluate the anti-aging effects of a cream containing EGF-DOTAP complex on human skin. Twentyeone Korean women completed a 12weeks study and were applied twice daily to the face. As compared with the vehicle control, EGF-DOTAP cream significantly improved the facial photo-damage score, skin roughness (R1), maximum roughness (R2), average roughness (R3, Ra), arithmetic roughness average (R5), and dermal density at 12 weeks. In conclusion, this study suggests that topical application of EGF-DOTAP complex exhibited significant improvement on skin aging by enhancing the permeation of EGF. LB1548 A pro-inflammatory environment modulates the human dermal fibroblast secretory phenotype: Implications for chronic wounds
BackgroundCT-P13 is an approved biosimilar to EU-approved and US-licensed Infliximab (INX) for the indications of rheumatoid arthritis (RA), adult and paediatric Crohn’s disease, adult and paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.ObjectivesThe purpose of this study was to demonstrate equivalence of efficacy and compare PK and safety profiles of CT-P13 and China-approved INX.MethodsIn this randomized, double blinded, multicenter, parallel-group, phase III study, patients with active RA who had been responding inadequately to methotrexate for at least 3 months, were randomized to receive either CT-P13 or China-approved INX. Patients were treated with doses of 3 mg/kg at Weeks 0, 2, 6, then every 8 weeks up to Week 54. Prior to dosing at Week 30, patients randomized to China-approved INX underwent a second randomization either to continue China-approved INX or to switch to CT-P13 at Week 30. Results of patients who underwent transition to CT-P13 were included in the China-approved INX group. The primary efficacy endpoint was change in DAS28 (CRP) from baseline to Week 14, which was analyzed using an analysis of covariance. Equivalence was determined if the 90% CI for the estimate of treatment difference was entirely contained within the predefined equivalence margin of -0.6 to 0.6.Results270 patients were randomly assigned to 2 treatment groups in a 1:1 ratio (136 and 134 patients in the CT-P13 and China-approved INX groups, respectively) and 184 patients completed the study. The least square mean change (standard error) of DAS28 (CRP) from baseline to Week 14, -1.566 [0.1419] and -1.547 [0.1491], was similar between the CT-P13 and China-approved INX groups, respectively. The 90% CI for the estimate of treatment difference (-0.29, 0.25) was contained within the predefined equivalence margin, which demonstrated therapeutic equivalence between the groups. The mean actual values for DAS28 (CRP) decreased from baseline to Week 54 and were similar between the groups (Figure 1). Additional efficacy endpoints, including ACR responses (ACR20 at Week 14; 60.6%, 54.8% and at Week 54; 65.1%, 60.6% in the CT-P13 and China-approved INX groups, respectively), EULAR responses, CDAI, and SDAI, were similar between the groups, even after switching at Week 30. During the study, mean serum INX concentrations were similar between the groups. Between Weeks 14 and 22, mean (percent coefficient of variation) AUCτ were 11156333.615 (44.796) ng·h/mL and 11462884.280 (51.057) ng·h/mL, and Cmax,ss were 66577.2 (31.4) ng/mL and 66356.1 (21.0) ng/mL in the CT-P13 and China-approved INX groups, respectively, which were similar between the groups. Most treatment-emergent AEs were grade 1 or 2 in intensity. One malignancy was reported in the CT-P13 group and no deaths were reported. The proportions of patients with anti-drug antibodies were similar between the groups, even after switching at Week 30. The overall safety profile of CT-P13 was comparable to that of China-approved INX and no new safety issues were observed (Table 1).Table 1.Summary of Safety ResultsNumber of patients (%)CT-P13 (N=136)China-approved Infliximab (N=133)Treatment-emergent AEsTotal115 (84.6%)107 (80.5%)Related97 (71.3%)86 (64.7%)Treatment-emergent serious AEsTotal17 (12.5%)12 (9.0%)Related10 (7.4%)6 (4.5%)Infusion related reaction/ hypersensitivity/anaphylactic reactionsTotal(=Related)20 (14.7%)19 (14.3%)InfectionsTotal45 (33.1%)43 (32.3%)Related36 (26.5%)40 (30.1%)Note: Summary is presented for the safety population who received at least 1 dose (full or partial) of study drug.ConclusionThe study demonstrated that efficacy of CT-P13 is equivalent to that of China-approved INX. Also, the PK and safety profiles of CT-P13 were comparable to those of China-approved INX. No loss of efficacy or difference in safety or immunogenicity was observed after switching from China-approved INX to CT-P13 at Week 30.Disclosure of InterestsJonathan Kay Consultant of: Boehringer Ingelheim GmbH; Pfizer Inc.; Samsung Bioepis; Sandoz Inc., Grant/research support from: Pfizer Inc. (paid to UMass Chan Medical School), Xiaofeng Zeng Grant/research support from: Celltrion, Inc, Lin Chen Grant/research support from: Celltrion, Inc, Kaijiang Tang Grant/research support from: Celltrion, Inc, guixiu shi Grant/research support from: Celltrion, Inc, Lin Liu Grant/research support from: Celltrion, Inc, Lijun Wu Grant/research support from: Celltrion, Inc, Yi Liu Grant/research support from: Celltrion, Inc, Jiankang Hu Grant/research support from: Celltrion, Inc, Shengyun Liu Grant/research support from: Celltrion, Inc, Zheng Yi Grant/research support from: Celltrion, Inc, Sung Hyun Kim Employee of: Celltrion, Inc, YunJu Bae Employee of: Celltrion, Inc, JeeHye Suh Employee of: Celltrion, Inc, Seungjin Rhee Employee of: Celltrion, Inc, SeulGi Lee Employee of: Celltrion, Inc, Chankyoung Hwang Employee of: Celltrion, Inc
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