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Purpose of Review Dual immune checkpoint inhibition with ipilimumab plus nivolumab is currently the most effective, but also by far the most toxic treatment for advanced melanoma. Therefore, other combination partners that also lead to high and long-lasting responses but cause fewer adverse events were explored. Recent Findings Relatlimab, a LAG-3 blocking antibody, was investigated in combination with nivolumab in a phase 2/3 randomized double-blind trial (RELATIVITY-047) and could demonstrate significantly improved progression-free survival in treatment-naive advanced melanoma patients compared with nivolumab monotherapy. While the safety profile is more favorable than that of ipilimumab plus nivolumab, no significant survival benefit has yet been demonstrated with the new combination over nivolumab monotherapy. Summary The approval of relatlimab plus nivolumab by both the Food and Drug Administration and the European Medicines Agency expands the arsenal of treatment options for melanoma but raises new questions in clinical practice and a re-evaluation of currently established treatment standards and sequences.

Background and Objectives: Systemic administration of glucocorticoids is a mainstay therapy for various inflammatory diseases and may lead to hyperglycemia, which carries the risk of worsening preexisting diabetes and triggering steroid-induced diabetes. Therefore, we aimed to identify patients at risk and to quantify severity of steroid-induced hyperglycemia (SIH) by continuous glucose monitoring (CGM) in hospitalized patients needing systemic glucocorticoid treatment. Patients and Methods: This prospective study included 51 steroid-naive, dermatological patients requiring systemic high-dose glucocorticoid treatment at the Department of Dermatology of the University Hospital Essen. After careful diabetes-specific assessment at admission, glucose monitoring was performed using a CGM system and glucose profile was analyzed in patients with and without SIH. Results: SIH occurred in 47.1% of all treated patients, and a relevant part of patients with initial normoglycemia developed SIH (2/10 patients). Doubling of SIH incidence was observed with each severity grade of dysglycemia (4/10 in prediabetes; 9/10 in diabetes). Patients with SIH spend nearly 6 hours daily above targeted glucose range, and severe hyperglycemia was observed for 1.2 hours/day. Conclusions: Our study underlines the need for dedicated glucose monitoring in dermatologic patients on systemic glucocorticoid therapy by demonstrating its impact on glucose metabolism.

Additional Material and Methods. Fluorescence microscopy of TUNEL and Ki67: Primary mice astrocytes or microglia were seeded on cover glasses. After stimulation for 24 h, the cells werr fixed with 4% paraformaldehyde. Subsequently, the cells were permeabilized with 0.1% Triton X in 0.1% sodium citrate for 3 min at 4°C. Then, the slices were incubated at 37°C for 1 h with TUNEL reaction mixture according the manufacturer’s protocol (In Situ Cell Death Detection Kit, Roche Diagnostics, Mannheim, Germany). After washing with PBS and blocking with 1.5 BSA in PBS for 10 min, the slices were incubated at 4°C about the night with Ki67 antibody (rabbit polyclonal; ab15580, abcam, UK). Finally, the slices were incubated with anti-rabbit Cy3 (AP132C, Millipore, Darmstadt, Germany) for 1 h at room temperature. Nuclear counter-staining was performed with Diamidino-2-phenylindole dihydrochloride DAPI (Sigma 9542, Munich, Germany). Cells were digitally photographed using a Keyence digital microscope (BZ-9000, Neu Isenburg, Germany). Ki67+ positive cells were counted for each treatment, where five 63×fields were evaluated. The proliferation index was determined by the number of positive cells expressing Ki67 divided by the total number of cells in each field. (DOCX 16 kb)

Mediators of inflammation 2016, 7678542 (2016). doi:10.1155/2016/7678542, Published by Hindawi Publishing Corp., Sylvania, Ohio

Antimicrobial peptides (AP) are important components of the innate immune system, yet little is known about their expression and function in the brain. Our previous work revealed upregulated gene expression of cathelicidin-related AP (CRAMP) following bacterial meningitis in primary rat glial cells as well as bactericidal activity against frequent meningitis-causing bacteria. However, the effect of cathelicidin expression on the progression of inflammation and mortality in bacterial meningitis remains unknown. Therefore, we used CRAMP-deficient mice to investigate the effect of CRAMP on bacterial growth, inflammatory responses and mortality in meningitis. Meningitis was induced by intracerebral injection of type 3 Streptococcus pneumoniae. The degree of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time RT-PCR. CRAMP deficiency led to a higher mortality rate that was associated with increased bacterial titers in the cerebellum, blood and spleen as well as decreased meningeal neutrophil infiltration. CRAMP-deficient mice displayed a higher degree of glial cell activation that was accompanied by a more pronounced proinflammatory response. Taken together, this work provides insight into the important role of CRAMP as part of the innate immune defense against pathogens in bacterial CNS infections. © 2013 S. Karger AG, Basel

During bacterial infections, antimicrobial peptides are synthesised as an important part of the innate immune system. However, expression and function in the central nervous system (CNS) need further investigations. The aim of this study was to examine the involvement of the pattern-recognition-receptor toll-like receptor 9 (TLR9) in the expression of the cathelin-related antimicrobial peptide (CRAMP) and to characterise the participating signal transduction pathways. In primary TLR9 deficient and wildtype mice astrocytes as well as microglia cells, the expression of CRAMP after treatment with the TLR9 agonist unmethylated cytosine-guanine oligodeoxynucleotide motifs (CpG-DNA) was examined in vitro. In vivo CRAMP expression after intraventricular infusion of CpG-DNA in TLR9 deficient and wildtype mice as well as in mice with pneumococcal meningitis localised in glial cells was determined. Furthermore, the regulation of different signal transduction pathways involved in CpG-DNA-induced CRAMP expression in glial cells was analysed. An in vitro and in vivo CpG-DNA-induced increase of CRAMP expression in astrocytes and microglia cells using real time RT-PCR and immunofluorescence was demonstrated. Different signal transduction pathways such as mitogen-activated protein kinases and inflammatory mediated pathways are involved in the expression of CRAMP in primary glial cells. Interestingly, TLR9-deficient glial cells showed a reduced but not completely abolished CRAMP mRNA expression and ERK1/2 phosphorylation in response to CpG-DNA treatment. On the other side in vivo, TLR9 deletion did not change CRAMP expression after bacterial infection. In conclusion, our results show that TLR9 can induce the expression of antimicrobial peptides such as CRAMP in response to bacterial DNA motifs in primary glial cells. Additional findings suggest also that CpG-DNA-induced effects are not only mediated by TLR9, but also mediated by other pattern recognition receptors.

Polymers 4(1), 539-560 (2012). doi:10.3390/polym4010539, Published by Molecular Diversity Preservation International, Basel