Abstract Introduction Although targeting human epidermal growth factor receptor 2 (HER2) is a meaningful treatment in HER2-positive breast cancer, ultimately resistance develops. Androgen receptor (AR) expression and immune cell infiltration are thought to be involved in trastuzumab response and may, therefore, be of interest as additional targets for therapy in HER2-positive breast cancer. Aim To improve insights into the presence among AR expression, immune cell infiltration and HER2, we analysed HER2-positive breast tumours. Methods Primary tumours of 221 patients treated with trastuzumab for metastatic disease were selected. HER2 status was centrally confirmed. AR, T-cells (CD3 and CD8), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 immunohistochemical staining and M2 tumour-associated macrophages (TAMs; CD68 and CD163) immunofluorescence were performed. Tumour-infiltrating lymphocytes were evaluated by haematoxylin and eosin staining. Results Sufficient tumour material was available for 150 patients. Oestrogen receptor was expressed in 51.3% of the tumours and AR in 81.3% of the tumours. AR expression was inversely correlated with M2 TAM (Pearson's r = −0.361, P < 0.001), CD3+ (r = −0.199, P < 0.030) and CD8+ (r = −0.212, P < 0.021) T-cell infiltration. Clustering analysis showed high immune cell infiltration in AR low-expressing tumours, and low immune cell infiltration in AR-high expressing tumours. Conclusion AR expression inversely correlates with immune cell infiltration in HER2-positive breast cancer.

Summary Background Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis. Methods We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759. Findings Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3–54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred. Interpretation Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis. Funding Janssen Research & Development.

Abstract We have investigated the protein interactions involved in the assembly of pancreatic β-cell ATP-sensitive potassium channels. The channels are a heterooligomeric complex of pore-forming Kir6.2 subunits and sulfonylurea receptor (SUR1) subunits. SUR1 belongs to the ATP binding cassette (ABC) family of proteins and has two nucleotide binding domains (NBD1 and NBD2) and 17 putative transmembrane (TM) sequences. Previously we showed that co-expression in a baculovirus expression system of two parts of SUR1 divided at Pro1042 between TM12 and 13 leads to restoration of glibenclamide binding activity, whereas expression of either individual N- or C-terminal domain alone gave no glibenclamide binding activity [M.V. Mikhailov and S.J.H. Ashcroft (2000) J. Biol. Chem. 275, 3360–3364]. Here we show that the two half-molecules formed by division of SUR1 between NBD1 and TM12 or between TM13 and 14 also self-assemble to give glibenclamide binding activity. However, deletion of NBD1 from the N-part of SUR1 abolished SUR1 assembly, indicating a critical role for NBD1 in SUR1 assembly. We found that differences in glibenclamide binding activity obtained after co-expression of different half-molecules are attributable to different amounts of binding sites, but the binding affinities remained nearly the same. Simultaneous expression of Kir6.2 resulted in enhanced glibenclamide binding activity only when the N-half of SUR1 included TM12. We conclude that TM12 and 13 are not essential for SUR1 assembly whereas TM12 takes part in SUR1 Kir6.2 interaction. This interaction is specific for Kir 6.2 because no enhancement of glibenclamide binding was observed when half-molecules were expressed together with Kir4.1. We propose a model of KATP channel organisation based on these data.