A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

(211)At-antiCD33 in NMRI nu/nu mice. Biodistribution, in vivo stability and radiotoxicity.

UNLABELLED: The aim of this study is to verify the in vivo stability, to determine the biodistribution and to estimate the unspecific radiotoxicity of an (211)At-labelled CD33-antibody ((211)At-antiCD33) in mice with a view to therapeutic application in treating leukaemia. ANIMALS, METHODS: (211)At was produced via the (209)Bi(a,2n)(211)At reaction and was linked via 3-(211)At-succinimidyl-benzoate to the antiCD33-antibody. The biodistribution and the in vivo stability in serum were determined after i.v.-injection in NMRI nu/nu-mice. For toxicity experiments, mice received either three times 315-650 kBq (211)At-antiCD33 or unlabelled antibody and NaCl-solution respectively. RESULTS: (211)At-antiCD33 showed a characteristic biodistribution complying with the unspecific antibody retention in the reticular endothelial system. The largest proportion of radioactivity remained in blood and blood-rich tissues with a minor accumulation in the thyroid and stomach. After 21 h, >85% of activity in serum still represented intact antibody. Mice showed no difference in unspecific toxicity of (211)At-labelled antibodies over six months compared to those treated with unlabelled antibody and NaCl-solution respectively, with regard to histopathologic lesions, survival time, behaviour and haemograms. CONCLUSION: The radiolabelling method yielded adequate in vivo stability of (211)At-antiCD33. Biodistribution with rapid elimination of free (211)At via kidneys and urine complies with requirements for targeted therapy. Activity doses potentially required for treatment do not elicit radiotoxicity to normal organs in mice. Further development is required to enhance the apparent specific activity and to verify the efficacy in an adequate animal model before phase I clinical studies in leukaemia can be envisaged.

Identification and characterization of the genes encoding human and mouse osteoactivin.

Osteoactivin (OA) is more highly expressed in the bones of osteopetrotic mutant rats (op/op) than in those of their normal littermates and is the homologue of human nmb, a cDNA more highly expressed in melanoma-derived cell lines of low metastatic potential, and of mouse DC-HIL, which has been implicated in endothelial cell adhesion. The human OA gene is found on chromosome 7p15.1 and consists of 11 exons spanning 28.3 kb. Murine OA is encoded by a highly similar gene of 11 exons spanning 20.2 kb on mouse chromosome 6. Human OA uses the same transcriptional initiation site in both bone and kidney as was reported for melanoma cells. OA is expressed in primary human and mouse osteoblast cultures at all stages of differentiation, with increased levels observed concurrently with the expression of osteoblast phenotype markers. OA is also expressed in a wide variety of human and mouse tissues as determined by RT-PCR analysis. Immunohistochemical investigation of OA expression in late mouse embryonic development showed very high, cell-specific expression in the nervous system, basal layer of the skin, germinal cells of hair follicles, and in the forming nephrons of the kidney. Continuing investigation of the cell-specific expression of OA in bone as well as in other tissues will lead to a better understanding of its function in the development of these cell types.

A poorly differentiated germ cell tumor (seminoma) in a Long Evans rat.

A large neoplasm that replaced 1 testis of a Long Evans Rat was noted at the final necropsy of a dietary 2-yr study. By light microscopy, the morphological features were consistent with a poorly differentiated seminoma. Ultrastructurally, the cells were polygonal, had a round nucleus, had straight cellular boundaries, and bore no resemblance to Sertoli cells. Although there was little evidence of spermatocytic differentiation, the presence of proacrosomal granules and vesicles, prominent Golgi apparatus, tight intercellular junctions, and a few centriolar pairs without axoneme development, in conjunction with the absence of lipid droplets or abundant smooth endoplasmic reticulum, supported the diagnosis of seminoma rather than Leydig cell tumor. The cells were S-100- and vimentin-positive, although cytokeratin- and alpha-fetoprotein-negative. Seminomas are extremely rare neoplasms in rats; this is the first report in this strain and the first extensive analysis of a rat seminoma without spermatocytic differentiation.

Allure of negative feedback: self-verification strivings among depressed persons.

We propose that people with negative self-views are rejected because they gravitate to partners who view them unfavorably. In relation to nondepressed college students (n = 28), depressives (n = 13) preferred interaction partners who evaluated them unfavorably (Study 1). Similarly, in relation to nondepressives (n = 106), depressives (n = 10) preferred friends or dating partners who evaluated them unfavorably (Study 2). Dysphorics (n = 6) were more inclined to seek unfavorable feedback from their roommates than were nondepressives (n = 16); feedback-seeking activities of dysphorics were also associated with later rejection (Study 3). Finally, people with negative self-views (n = 37) preferentially solicited unfavorable feedback, although receiving such feedback made them unhappy, in comparison with people with positive self-views (n = 42; Study 4). It seems a desire for self-verification compels people with negative self-views to seek unfavorable appraisals.

Relating acoustic properties to perceptual responses: a study of Swedish voiced stops.

Perception models based on different kinds of acoustic data were compared with respect to their capacity to predict perceptual confusions between the Swedish stops [b,d,d,g] in systematically varied vowel contexts. Fragments of VC:V utterances read by a male speaker were presented to listeners. The resulting confusions were especially numerous between short stimulus segments following stop release, and formed a regular pattern depending mainly on the acute/grave dimension of the following vowel. The acoustic distances calculated were based on: (1) filter band spectra; (2) F2 and F3 at the CV boundary and in the middle of the following vowel; (3) the duration of the burst (= transient + noise section). Both the spectrum-based and the formant-based models provided measures of acoustic distance (dissimilarity) that revealed regular patterns. However, the predictive capacity of both models was improved by including the time-varying properties of the stimuli in the distance measures. The highest correlation between predicted and observed percent confusions, r = 0.85, was obtained with the formant-based model in combination with burst length data. The asymmetries in the listeners' confusions were also shown to be predictable, given acoustic data on the following vowel.

Agreeable fancy or disagreeable truth? Reconciling self-enhancement and self-verification.

Three studies asked why people sometimes seek positive feedback (self-enhance) and sometimes seek subjectively accurate feedback (self-verify). Consistent with self-enhancement theory, people with low self-esteem as well as those with high self-esteem indicated that they preferred feedback pertaining to their positive rather than negative self-views. Consistent with self-verification theory, the very people who sought favorable feedback pertaining to their positive self-conceptions sought unfavorable feedback pertaining to their negative self-views, regardless of their level of global self-esteem. Apparently, although all people prefer to seek feedback regarding their positive self-views, when they seek feedback regarding their negative self-views, they seek unfavorable feedback. Whether people self-enhance or self-verify thus seems to be determined by the positivity of the relevant self-conceptions rather than their level of self-esteem or the type of person they are.