Bioplex analysis of skin infiltrating T cells.

<p>T cells infiltrating either the psoriatic plaque or the induced ACD lesion were stimulated with aCD3/aCD28 antibodies and cell-free supernatant was used for Bioplex analysis with 27 different analytes. Detected proteins were grouped according to association with the Th2 line (<b>A</b>), Th1 line (<b>B</b>), Th17 line (<b>C</b>), innate immunity (<b>D</b>) and growth factors (<b>E</b>). Shown are boxplots from five patients.</p

Induction of allergic contact dermatitis in psoriasis patients.

<p><b>A</b> Dermatitis 5 days after application of a nickel patch test in close proximity to a psoriasis plaque; <b>B</b> Comparison of reaction severity and time course of nickel patch test reactions to nickel in sensitized psoriasis patients (n = 14, mean is shown in blue line) and non-psoriatic individuals (n = 10, mean is shown in black dashed lines). Standard deviation is given by dotted lines.</p

Clincial characterization of patients enrolled into the study.

<p>Clincial characterization of patients enrolled into the study.</p

Immunohistochemical comparison of psoriasis and ACD reactions in the same patient.

<p>Representative immunohistochemical stainings of psoriasis and ACD biopsy sections obtained from the same patient (right panel) and quantification of positive cells per visual field of all included patients (n = 10) (boxplots in left panel).</p

ACD and psoriasis are independent, stimulus-driven immune reactions.

<p>Nickel patch tests were used to induce ACD lesions in close proximity to or on top of a psoriasis plaque (n = 11). <b>A</b> Representative clinical course of psoriasis, ACD, and psoriasis/ACD mixed reaction in one patient. <b>B</b> Subjective clinical evaluation was confirmed investigating the local blood flow as indicator for severity of inflammation via laser doppler imaging at day 0, day 4, day 7 and day 21 (<b>B</b>). <b>C</b> Changes in local PASI, erythema, infiltrate and squamation were determined for the nickel treated psoriasis plaque before and 21 days after nickel challenge (n = 11) and presented as boxplots.</p

Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects

Clinically non-involved skin of psoriasis patients is altered regarding metabolism and proliferation.

<p>Signaling pathway analysis of clinically non-involved skin of psoriasis patients (n = 8) versus healthy skin of non-psoriatic individuals (n = 10). Shown are the most significant hits for the Gene Ontology term “biological process”. The bar size indicates the level of significance for each pathway (negative log2 p-value), the vertical line shows the 0.05 significance level.</p

Allergic contact dermatitis in psoriasis patients: typical, delayed, and non-interacting.

Psoriasis is characterized by an apoptosis-resistant and metabolic active epidermis, while a hallmark for allergic contact dermatitis (ACD) is T cell-induced keratinocyte apoptosis. Here, we induced ACD reactions in psoriasis patients sensitized to nickel (n = 14) to investigate underlying mechanisms of psoriasis and ACD simultaneously. All patients developed a clinically and histologically typical dermatitis upon nickel challenge even in close proximity to pre-existing psoriasis plaques. However, the ACD reaction was delayed as compared to non-psoriatic patients, with a maximum intensity after 7 days. Whole genome expression analysis revealed alterations in numerous pathways related to metabolism and proliferation in non-involved skin of psoriasis patients as compared to non-psoriatic individuals, indicating that even in clinically non-involved skin of psoriasis patients molecular events opposing contact dermatitis may occur. Immunohistochemical comparison of ACD reactions as well as in vitro secretion analysis of lesional T cells showed a higher Th17 and neutrophilic migration as well as epidermal proliferation in psoriasis, while ACD reactions were dominated by cytotoxic CD8+ T cells and a Th2 signature. Based on these findings, we hypothesized an ACD reaction directly on top of a pre-existing psoriasis plaque might influence the clinical course of psoriasis. We observed a strong clinical inflammation with a mixed psoriasis and eczema phenotype in histology. Surprisingly, the initial psoriasis plaque was unaltered after self-limitation of the ACD reaction. We conclude that sensitized psoriasis patients develop a typical, but delayed ACD reaction which might be relevant for patch test evaluation in clinical practice. Psoriasis and ACD are driven by distinct and independent immune mechanisms.peerReviewe

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients