Background Though patient needs are key drivers of treatment decisions, they are rarely systematically investigated in routine care.Objective This study aimed at analysing needs and expectations from the patient perspective in the German and Swiss psoriasis registries PsoBest and Swiss Dermatology Network of Targeted Therapies (SDNTT) with respect to treatment choice, age and gender.Methods The German and Swiss psoriasis registries observe patients recruited at first-time use of systemic drugs.Within 10 years, clinical [Psoriasis Area Severity Index (PASI), Body Surface Area (BSA)] and patient-reported outcomes are documented, including the Dermatology Quality of Life Index (DLQI) and the Patient Benefit Index (PBI), characterizing patient needs for treatment. The analysis data set includes n = 4894 patients from PsoBest and n = 449 from SDNTT with mean follow-up time of 7.5 months.Results A total of 5343 patients registered between 2008 and 2016 were included in the analyses (at baseline: 59.6% male, mean age 47.6 years AE 14.5, PASI 14.2 AE 9.7, BSA 22.7 AE 19.7, DLQI 11.3 AE 7.2). The most important patient needs were to 'get better skin quickly' and to 'be healed of all skin defects'.Subgroup analyses by age revealed significant differences in needs, especially higher needs regarding social impairments in patients younger than 65 years.Patients 65 years or older attributed more importance to sleep quality, less dependency on medical visits, fewer sideeffects and confidence in the therapy. Out of 25 items reflecting patient needs, 20 items were rated significantly more important by women than men, with the greatest differences regarding feeling of depression, sleep quality and everyday productivity. Divided by treatment, needs were rated differently, recommending individualized and targeted choice of therapy.Conclusion Age and gender stratify patient needs. Women showed higher expectations and rated specific needs in psoriasis treatment higher than men. Analysing the patient needs on an individual level will facilitate shared decisions by patient and physician in finding the optimal personalized treatment.

The PIDDosome, a multiprotein complex constituted of the ‘p53-induced protein with a death domain (PIDD), ‘receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain' (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-κB) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.

LCN2 drives ethanol-induced neutrophilic inflammation and propagates the development of ALD. Despite a critical role for LCN2 in immunity and infection, pharmacological neutralisation of LCN2 might be of promise in ALD.

Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca influx through high voltage-gated Ca channels (HVCCs). Ca influx also regulates insulin synthesis and insulin granule priming and contributes to β-cell electrical activity. The HVCCs are multisubunit protein complexes composed of a pore-forming α and auxiliary β and αδ subunits. αδ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of αδ-1, the dominant αδ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the αδ-1 subunit reduces the Ca currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca influx alters the kinetics and amplitude of the global Ca response to glucose in pancreatic islets and significantly reduces insulin release in both sexes. The progression of diabetes in males is aggravated by a selective loss of β-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most αδ-1 female mice. Together, these findings demonstrate that the loss of the Ca channel αδ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.

Transforming growth factor beta (TGF-b)-and Interleukin-2 (IL-2)-mediated signaling enables the generation and expansion of induced regulatory T (iTreg) cells that carry high hopes for the treatment of chronic inflammatory and autoimmune diseases. Knowledge about factors stabilizing their lineage commitment and lifespan, however, is limited. Here, we investigated the behavior of iTreg cells, derived from apoptosis-defective mouse mutants, during activated cell autonomous cell death, triggered by cytokine-deprivation, or activation-induced cell death (AICD) after restimulation of the T-cell receptor, and compared these responses with those of effector T cells. We observed that iTreg cells were much more sensitive to IL-2-deprivation but poorly susceptible to AICD. In fact, when apoptosis was compromised, T-cell receptor (TCR)-religation resulted in methylationindependent, ERK-and PI3K/mTOR-mediated loss of Foxp3 expression, impaired suppressive capacity and effector cytokine production. Although iTreg cells prevented colitis induction they rapidly lost Foxp3-GFP expression and gained ability to produce effector cytokines thereby imposing Th1 cell fate on resident effector cells. Surprisingly, iTreg cell conversion itself was limited by TGF-b-mediated Bim/Bcl2L11-dependent apoptosis. Hence, the very same cytokine that drives the generation of iTreg cells can trigger their demise. Our results provide novel insights in iTreg cell biology that will assist optimization of iTreg-based therapy.