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This file contains transcripts induced by type I interferon (S1) or regulated by p53 in response to DNA damage (S2).

Because of imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Whereas complete lack of RER is embryonically lethal, partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here, we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.Significance: Selective inactivation of ribonucleotide excision repair by loss of RNase H2 in the murine epidermis results in spontaneous DNA damage, type I interferon response, skin inflammation, and development of squamous cell carcinoma. Cancer Res; 78(20); 5917–26. ©2018 AACR.

Spontaneous type I IFN response and inflammation in Rnaseh2EKO skin.

This file contains histology of skin and skin lesions of RNaseH2EKO mice with intact or defective Trp53 alleles.

Histopathological characterization of mutant skin

In this paper we consider the strategic asset allocation of an insurance company. This task can be seen as a special case of portfolio optimization. In the 1950s, Markowitz proposed to formulate portfolio optimization as a bicriteria optimization problem considering risk and return as objectives. However, recent developments in the field of insurance require four and more objectives to be considered, among them the so-called solvency ratio that stems from the Solvency II directive of the European Union issued in 2009. Moreover, the distance to the current portfolio plays an important role. While literature on portfolio optimization with three objectives is already scarce, applications with four and more objectives have not yet been solved so far by multi-objective approaches based on scalarizations. However, recent algorithmic improvements in the field of exact multi-objective methods allow the incorporation of many objectives and the generation of well-spread representations within few iterations. We describe the implementation of such an algorithm for a strategic asset allocation with four objective functions and demonstrate its usefulness for the practitioner. Our approach is in operative use in a German insurance company. Our partners report a significant improvement in their decision making process since, due to the proper integration of the new objectives, the software proposes portfolios of much better quality than before within short running time., 24 pages, 4 figures, 5 tables

The risk of a future payoff is commonly quantified by calculating the costs of a hedging portfolio such that the resulting position is acceptable, i.e. that it passes a capital adequacy test. A multi-asset risk measure describes the minimal external capital which has to be raised into multiple eligible assets to make a future risky position acceptable. Recently, the alternative methodology of intrinsic risk measures was introduced in the literature. These ask for the minimal proportion of the risky position which has to be reallocated to pass the capital adequacy test, i.e. only internal capital is used. We combine these two concepts and call this new type of risk measure a multi-asset intrinsic risk measure. It allows to secure the risky position by external capital as well as reallocating liquid parts of the portfolio as an internal rebooking. We investigate several properties to demonstrate similarities and differences to the two aforementioned classical types of risk measures. We find that diversification reduces risk only under an additional but economically motivated assumption on the risky positions. With the help of Sion’s minimax theorem we also prove a dual representation for multi-asset intrinsic risk measures. Finally, we determine capital requirements in a model motivated by the Solvency II methodology.

Generalized linear models are common instruments for the pricing of non-life insurance contracts. They are used to estimate the expected frequency and severity of insurance claims. However, these models do not work adequately for extreme claim sizes. To accommodate for these extreme claim sizes, we develop the threshold severity model, that splits the claim size distribution in areas below and above a given threshold. More specifically, the extreme insurance claims above the threshold are modeled in the sense of the peaks-over-threshold methodology from extreme value theory using the generalized Pareto distribution for the excess distribution, and the claims below the threshold are captured by a generalized linear model based on the truncated gamma distribution. Subsequently, we develop the corresponding concrete log-likelihood functions above and below the threshold. Moreover, in the presence of simulated extreme claim sizes following a log-normal as well as Burr Type XII distribution, we demonstrate the superiority of the threshold severity model compared to the commonly used generalized linear model based on the gamma distribution.

Berichtet wird uber den bemerkenswerten Verlauf eines fazialen Ulkus bei einer Patientin unter Therapie mit Prednisolon im Rahmen eines M. Crohn. Bei initial unklarer Diagnose zeigte sich ein rasch progredienter Befund trotz dreifach antiinfektiver Therapie (antiviral, antibiotisch, antimykotisch). Eine Infektion mit Orthopoxviren konnte anhand umfangreicher Diagnostik im Verlauf bestatigt werden, relevante Differentialdiagnosen wurden ausgeschlossen. Nach umfangreicher nekrotischer Umwandlung kam es nach Monaten zu einer narbigen Abheilung. Kuhpockeninfektionen kommen in Deutschland immer wieder vor und sind eine klinisch relevante Zoonose. Am haufigsten erfolgt die Ubertragung durch Katzen und Nagetiere. Differenzialdiagnostisch kommen verschiedenste teilweise seltene Erreger ursachlich in Betracht, die hier anhand klinischer und histopathologischer Merkmale diskutiert werden. Hierzu zahlen bakterielle, mykobakterielle, mykotische und parasitare Infektionen. Insbesondere die kutane Leishmaniose ist aufgrund steigender Inzidenz hierzulande explizit zu nennen. Da infektiose faziale Ulzera bei inadaquater Therapie zu lebensgefahrlichen Komplikationen und ausgedehnter entstellender Narbenbildung fuhren konnen, ist eine zeitkritische kalkulierte Therapieeinleitung vordringlich.

In this paper, we are concerned with the Monte Carlo valuation of discretely sampled arithmetic and geometric average options in the Black-Scholes model and the stochastic volatility model of Heston in high volatility environments. To this end, we examine the limits and convergence rates of asset prices in these models when volatility parameters tend to infinity. We observe, on the one hand, that asset prices, as well as their arithmetic means converge to zero almost surely, while the respective expectations are constantly equal to the initial asset price. On the other hand, the expectation of geometric means of asset prices converges to zero. Moreover, we elaborate on the direct consequences for option prices based on such means and illustrate the implications of these findings for the design of efficient Monte-Carlo valuation algorithms. As a suitable control variate, we need among others the price of such discretely sampled geometric Asian options in the Heston model, for which we derive a closed-form solution.

Journal der Deutschen Dermatologischen Gesellschaft : JDDG = Journal of the German Society of Dermatology 19(9), 1371-1395 (2021). doi:10.1111/ddg.14491, Published by Wiley-Blackwell, Berlin

Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1., Gerber, Russ et al. show that the H3.3 chaperone Daxx, which represses endogenous retroviral and retrotransposable elements, acts as an epigenetic barrier to control haematopoietic progenitor plasticity and protect against PU.1-mediated inflammation.

In this paper, we are concerned with the Monte Carlo valuation of discretely sampled arithmetic and geometric average options in the Black-Scholes model and the stochastic volatility model of Heston in high volatility environments. To this end, we examine the limits and convergence rates of asset prices in these models when volatility parameters tend to infinity. We observe on the one hand that asset prices as well as their arithmetic means converge to zero almost surely, while the respective expectations are constantly equal to the initial asset price. On the other hand, the expectation of geometric means of asset prices converges to zero. Moreover, we elaborate on the direct consequences for option prices based on such means and illustrate the implications of these findings for the design of efficient Monte-Carlo valuation algorithms. As a suitable control variate, we need among others the price of such discretely sampled geometric Asian options in the Heston model, for which we derive a closed-form solution.

Background Palmoplantar pustular psoriasis (PPP) is a recalcitrant chronic skin disease affecting the palms and soles. Objective To identify and characterize pathogenetic players in PPP. Methods Clinical and anamnestic data as well as skin and blood samples of 60 PPP patients were collected. Healthy participants served as controls. Analysis of patient samples and cultured primary skin cells was performed by ELISA, qRT-PCR, and immunohistochemistry. Results Upon screening of blood mediators in PPP patients, lipocalin 2 (LCN2) emerged as being significantly upregulated compared to healthy participants. LCN2 blood levels were independent of age, sex, or concomitant psoriasis vulgaris. Keratinocytes in PPP skin lesions were important LCN2 producers. In vitro, LCN2 production of these cells was upregulated by IL-1β and further enhanced by IL-17 and TNF-α, while IL-22 had no effect. Accordingly, a positive relationship between blood IL-1β and LCN2 levels was evident in PPP. LCN2 blood levels also showed a positive correlation with PPP pustule score, Dermatology Quality of Life Index and blood levels of the pro-atherogenic molecule resistin. Conclusions In PPP, increased blood levels of LCN2 indicate an important activity of IL-1β in the epidermis, may contribute to skin neutrophil infiltration, and may point to an increased pro- atherosclerosis risk.

Cliquet-style options in different variants are basic building blocks in select products which are offered by German life insurance companies. We present both an analytical pricing approximation via the central limit theorem and a corresponding control variate Monte Carlo approach for their valuation. The control variate approach turns out to be a good alternative to the integral representation of Bernard and Li (SIAM J Financ Math, 4:353-371, 2013). Further, it can be modified to increase the efficiency of pricing cliquet-style options in the Heston price setting.

Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.

Background: Culminating evidence over the past decade regarding management of systemic lupus erythematosus (SLE) called for an update of the 2008 EULAR recommendations for the treatment of the disease. Objectives: Systematic review of the literature (SLR) to inform the 2019 EULAR recommendations for the management of SLE. Methods: SLR of Pubmed from 01/2007 to 12/2017 for questions (selected through Delphi excercise) regarding: i) efficacy/safety of different drugs used in SLE, ii) treatment of specific manifestations, iii) monitoring and treatment goals and iv) comorbidities and adjunct therapy. Evidence was categorised based on design and validity of available studies [Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (LoE)] and strength of statements was graded [Grading of recommendation (GoR), assessment, development and evaluations, GRADE)]. Results: Main topics supported by strong evidence base included: Association of hydroxychloroquine (HCQ) use with favourable outcomes (LoE 1b, GoR A), belimumab for extrarenal disease (LoE 1a, GoR A), efficacy of antimalarials in skin disease (LoE 1a, GoR A), mycophenolate mofetil (MMF) for induction and maintenance therapy of lupus nephritis (LN) and cyclophosphamide (CYC) in severe LN (LoE 1b, GoR A). Weak evidence supported the value of repeat kidney biopsy in refractory LN (LoE 4, GoR C), all second-line agents for skin disease (LoE 4, GoR C) and efficacy of most first and second-line treatments for thrombocytopenia (LoE 4, GoR C). Moderate LoE was found for all other questions (Table). Conclusion: A SLR for the treatment of SLE found the highest LoE for benefits of HCQ, efficacy of belimumab for extrarenal disease and MMF and IV-CYC in LN. Acknowledgement: European League Against Rheumatism Disclosure of Interests: Antonis Fanouriakis Paid instructor for: Amgen, GSK, Speakers bureau: Abbvie, Enorasis, Genesis Pharma, Myrto Kostopoulou: None declared, Alessia Alunno: None declared, Martin Aringer Grant/research support from: Roche, Consultant for: AstraZeneca and Eli Lilly, Ingeborg Bajema Consultant for: GSK, John N. Boletis: None declared, Ricard Cervera: None declared, Andrea Doria: None declared, Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Marcello Govoni Paid instructor for: Pfizer, Roche, Speakers bureau: Pfizer, Abbvie, MSD, Roche, Eli-Lilly, Celgene, Sanofi, Janssen, Frederic Houssiau: None declared, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, Marios Kouloumas: None declared, Annegret Kuhn Grant/research support from: Biogen, Galderma, GlaxoSmithKline, LeoPharma, Speakers bureau: La Roche Posay, Janni Lisander Larsen: None declared, Kirsten Lerstrom: None declared, Gabriela Moroni: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB, Matthias Schneider Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Speakers bureau: Chugai, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Elisabet Svenungsson: None declared, Vladimir Tesar: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Anne Troldborg: None declared, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Jorg Wenzel Grant/research support from: GSK, Incyte, Consultant for: Biogen, Leo, Paid instructor for: Novartis, George Bertsias: None declared, Dimitrios Boumpas: None declared

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.

Background Recommendations for the treatment of systemic lupus erythematosus (SLE) were published by EULAR in 2008. Advances in treatment strategies and goals called for an update of these recommendations, capitalizing on strengths and experience from previous projects. Objectives To update the EULAR recommendations for the management of SLE. Methods Systematic literature review (01/2007-12/2017) followed by Delphi method to form questions, elicit expert opinions and reach consensus. Results Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all lupus patients, at a dose not exceeding 5mg/kg real body weight. During chronic maintenance treatment, glucocorticoids should be minimized to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite tapering/discontinuation of glucocorticoids. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab may be considered in organ-threatening, refractory disease. Specific recommendations are also provided for the management of cutaneous, neuropsychiatric, haematological and renal disease (including the use of calcineurin inhibitors). SLE patients should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile, and preventative strategies be tailored accordingly. Conclusion Updated EULAR recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion. Acknowledgement European League against Rheumatism Disclosure of Interests Antonis Fanouriakis Paid instructor for: Amgen, GSK, Speakers bureau: Abbvie, Enorasis, Genesis Pharma, Myrto Kostopoulou: None declared, Alessia Alunno: None declared, Martin Aringer Grant/research support from: Roche, Consultant for: AstraZeneca and Eli Lilly, Ingeborg Bajema Consultant for: GSK, John N. Boletis: None declared, Ricard Cervera: None declared, Andrea Doria: None declared, Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Marcello Govoni Paid instructor for: Pfizer, Roche, Speakers bureau: Pfizer, Abbvie, MSD, Roche, Eli-Lilly, Celgene, Sanofi, Janssen, Frederic Houssiau: None declared, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, Marios Kouloumas: None declared, Annegret Kuhn Grant/research support from: Biogen, Galderma, GlaxoSmithKline, LeoPharma, Speakers bureau: La Roche Posay, Janni Lisander Larsen: None declared, Kirsten Lerstrom: None declared, Gabriela Moroni: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB, Matthias Schneider Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Speakers bureau: Chugai, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Elisabet Svenungsson: None declared, Vladimir Tesar: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Anne Troldborg: None declared, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Jorg Wenzel Grant/research support from: GSK, Incyte, Consultant for: Biogen, Leo, Paid instructor for: Novartis, George Bertsias: None declared, Dimitrios Boumpas: None declared

Background: Cutaneous lupus erythematosus (CLE) is an autoimmune disease with heterogenous subtypes presenting with inflammatory skin lesions, a histological pattern called “Interface-dermatitis” and enhanced type-1-interferon (IFN)-regulated JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway signaling. Despite deeper understanding of the pathogenesis still no specifically approved drugs for CLE exist. Objectives: The aim of our study was to investigate the effect of JAK1 selective inhibition as potential therapeutic approach for CLE in established preclinical models of cutaneous autoimmunity. Methods: The expression of IFN-regulated proteins and genes after JAK1 inhibitor treatment was analysed in cultured, stimulated immortalized and primary human epidermal keratinocytes. In addition the impact of JAK1 inhibition on CLE-like skin lesions in lupus prone MRL/lpr- and TREX1-knockout-mice was determined. Results: In vitro investigation revealed a significantly decreased gene- and protein expression of proinflammatory cytokines, in particular CXCL10 as key driver chemokine of lesional inflammation, and other pathophysiologic important IFN-regulated mediators in inflamed keratinocytes after treatment with JAK1 inhibitors. Moreover JAK1 inhibition generated an amelioration of skin lesions in lupus prone mice. Conclusion: Our findings indicate that inhibition of JAK1 results in a decreased chemokine expression, subsequent less cytotoxic T cell induced keratinocytic cell death leading to an improvement of lesional skin. By breaking the vicious inflammatory cycle JAK1 inhibitors appear to be promising agents as targeted therapy of CLE. Further investigation has to be performed in clinical trials. References [1] Wenzel, J.; Tuting, T. (2008): An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. In: The Journal of investigative dermatology 128 (10), S. 2392–2402. [2] Kuhn, A.; Landmann, A.; Wenzel, J. (2016): Advances in the treatment of cutaneous lupus erythematosus. In:Lupus 25 (8), S. 830–837. [3] Hornung, T.; Janzen, V.; Heidgen, F.-J.; Wolf, D.; Bieber, T.; Wenzel, J. (2014): Remission of recalcitrant dermatomyositis treated with ruxolitinib. In: The New England journal of medicine 371 (26), S. 2537–2538. [4] Klaeschen, AS.; Wolf, D.; Brossart, Peter; Bieber, T.; Wenzel, J. (2017): JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus. In:Experimental dermatology 26 (8), S. 728–730. Acknowledgement: The authors thank Nadine van Holt (University Hospital Bonn) for her most valuable support in preparation of the manuscript and Sandra Ferring-Schmitt and Sonja Sternberg for their great helpfulness in the laboratories. Disclosure of Interests: Tanja Fetter: None declared, Paul Smith Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Tugce Gul: None declared, Thomas Bieber: None declared, Jorg Wenzel Grant/research support from: GSK, Incyte, Consultant for: Biogen, Leo, Paid instructor for: Novartis

Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.