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Abstract Aims Aptamer BC 007, a 15‐mer single‐strand DNA oligonucleotide (5'‐GGTTGGTGTGGTTGG‐3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein‐coupled receptors (GPCR‐AAB), leading to the modulation of receptor‐mediated signalling cascades that induce pathophysiological states. Among the GPCR‐AAB, there are those directed against the β1‐adrenergic receptor (β1‐AAB) that are highly present in patients with dilated cardiomyopathy (DCM) and are increasingly accepted as disease drivers. Using Doberman Pinschers (DP) with DCM, which possess similarities with human DCM among these β1‐AAB positivity for that the disease‐driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing β1‐AAB, and the DP's outcome were investigated. Methods and results Fourteen client‐owned β1‐AAB‐positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 β1‐AAB‐positive DP with DCM not treated with BC 007 (Control 1) and 14 DP with DCM closely matched to the BC 007‐treated DP (Control 2), retrospectively selected from the institutional database of DP. After treatment, DP were monitored both echocardiographically, and for β1‐AAB, and survival curves were calculated. Based on clinical and laboratory examination, no adverse effects associated with BC 007 treatment were observed during the study. Forty‐eight hours after treatment, the DP's blood was free of β1‐AAB, which led to a reduction or stabilization of left ventricular end‐systolic volume (ESVI) during β1‐AAB free time in 10 of the treated DP. In one DP, where β1‐AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from β1‐AAB and improved the ESVI. Compared with the controls, DP treated with BC 007 showed a significantly longer survival time [572 days, interquartile range (IQR) 442–840 days] vs. Control group 1 (266 days, IQR 97–438 days; logrank: P = 0.009) and Control group 2 (229 days, IQR 174–319 days; logrank: P = 0.012). Conclusions Treatment with BC 007 for β1‐AAB neutralization was safe, resulted in a long‐lasting reduction of β1‐AAB combined with improved cardiac function and prolonged the survival of DP with DCM. Using a natural large animal model of DCM considered superior to small animal models of immunization‐induced cardiomyopathy, combined with a study design comparable with clinical trials, we believe that our results provide the basis for optimism that treatment with BC 007 might also be effective in human patients with DCM.

BackgroundAutoimmunity associated with autoantibodies against the β1-adrenergic receptor (β1-AAB) is increasingly accepted as the driver of human dilated cardiomyopathy (DCM). Unfortunately, there is a lack of animal models to extend the knowledge about β1-AAB autoimmunity in DCM and to develop appropriate treatment strategies.ObjectivesTo introduce an animal model, we investigated the β1-AAB associated autoimmunity in Doberman Pinscher (DP) with dilated cardiomyopathy, which has similarities to human DCM.Materials and methodsEighty-seven DP with cardiomyopathy in terms of pathological ECG and echocardiography (DoCM) and 31 dogs (at enrollment) without DoCM (controls) were analyzed for serum activity of β1-AAB with a bioassay that records the chronotropic response of spontaneously beating cultured neonatal rat cardiomyocytes to the DP's IgG. To locate the receptor binding site of β1-AAB and the autoantibody's sensitivity to inhibition, competing experiments with related blockers were performed with the bioassay. In controls that developed DoCM during follow-up, β1-AAB were analyzed during progress.ResultsFifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were β1-AAB positive. Of the controls that developed DoCM, 8 were β1-AAB positive (p = 0.044 vs. dogs remaining in the control group); their β1-AAB activity increased with the cardiomyopathy progress (pConclusionsDoberman Pinschers presented β1-AAB associated autoimmunity, similar as in the pathogenesis of human DCM. Consequently, DP could compensate the lack of animal models for the investigation of β1-AAB autoimmunity in human DCM.

[This corrects the article DOI: 10.1371/journal.pone.0192778.].

Dementia in general and Alzheimer's disease in particular is increasingly seen in association with autoimmunity being causatively or supportively involved in the pathogenesis. Besides classic autoantibodies (AABs) present in dementia patients, there is the new autoantibody class called functional autoantibodies, which is directed against G-protein coupled receptors (GPCRs; GPCR-AABs) and are seen as pathogenic players. However, less is known about dementia patients' burden with functional autoantibodies. We present here for the first time a study analyzing the prevalence of GPCR-AABs in patients with different dementia forms such as unclassified, Lewy body, vascular and Alzheimer's dementia. We identified the GPCR-AABs' specific targets on the receptors and introduced a neutralization strategy for GPCR-AABs. Patients with Alzheimer’s and vascular dementia carried GPCR-AABs targeting the second loop of the alpha1- and the first loop of the beta2-adrenergic receptors (α1-AABs; β2-AABs). The majority of patients with Lewy body dementia lacked any of the GPCR-AABs. In vitro, the function of the dementia-associated GPCR-AABs could be neutralized by the aptamer BC007. Due to the presence of GPCR-AABs in dementia patients mainly in those suffering from Alzheimer's and vascular dementia, the orchestra of immune players in these dementia forms, so far preferentially represented by the classic autoantibodies, should be supplemented by functional autoantibodies. As dementia-associated functional autoantibodies could be neutralized by the aptamer BC007, the first step was taken for a new in vivo treatment option in dementia patients who were positive for GPCR-AABs.

Metabolic syndrome and cardiomyopathies are long-term consequences of chemo- and radiotherapy and develop long after completing the initial tumor treatment. The slow progression of such late effects might be an indication of the involvement of autoimmune processes in the development of such follow-up consequences. Functionally active autoantibodies, which permanently stimulate relevant cell receptors, might be a crucial component. Here, we report the detection of functionally active agonistic autoantibodies such as the autoantibody against the adrenergic alpha1-receptor, the muscarinic M2-receptor, and the newly discovered autoantibody against the Mas-receptor in the plasma of a cancer survivor following chemotherapy treatment.

Summary Background: There is controversial discussion whether metastasis initiated by laparoscopy with carbon dioxide might be prevented by instillation of taurolidin or radical scavengers like the somatostatin analogue Octreotide. Therefore we evaluated the effects of laparoscopic lavage with taurolidin and Octreotide on liver metastasis after staging laparoscopy in ductal pancreatic cancer. Methods: In 60 Syrian hamsters pancreatic adenocarcinoma was induced by weekly subcutanous injection of 10 mg N-nitrosobis-2-oxopropylamin/kg body weight for 10 weeks. In the 16th week laparoscopic staging biopsy by use of carbon dioxide was performed. Finally animals underwent abdominal irrigation with saline (gr.1, n = 20), taurolidin (0.5%) (gr.2, n = 20) or Octreotide (gr.3, n = 20). In week 25 animals were sacrificed, pancreas and liver were analysed. Results: Size of pancreatic carcinomas was decreased in the taurolidin gr. compared to the other two groups. Furthermore the number of liver metastasis per animal was reduced after lavage with taurolidin (2 ± 2) and Octreotide (2.5 ± 2) compared to saline irrigation (4 ± 4) (p < 0.05). Additionally the incidence of port site metastases was significantly reduced in the taurolidin group. Activity of antioxidative enzyme superoxide dismutase (SOD) was increased while concentration of products of lipidperoxidation was decreased in non-metastatic liver after taurolidin irrigation compared to saline or Octreotide irrigation. Conclusions: Taurolidin irrigation during laparoscopy might be a new concept to reduce the number of liver metastasis and port site metastases in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background. To date, there have been no studies reliably showing an influence of the kidney on the concentration of troponins. We therefore analysed the concentration curves in patients after coronary artery bypass grafting (CABG) according to their dependence on renal function. Methods. We determined cardiac troponin I (cTnI), cardiac troponin T (cTnT) and creatinine in plasma in 28 patients after CABG. Discrimination into patients with normal (n = 13) and impaired (n = 15) renal function was based on creatinine clearance (Crea-Clear). The curves for cTnI and cTnT, as recorded by post-operative measurements, were approximated using mathematical functions. The curve parameters peak maximum (Pmax), peak position (Ppos), half-height breadth (HHB) and area under the curve (AUC) were established after this. Assuming an exponential function, the half-life (t1/2) of cTnI was determined from the declining part of the curve. Results. For both, cTnI and cTnT, significant differences in Pmax, Ppos, HHB and AUC were detected after curve approximation. The t1/2 values of cTnI were 25.1 h (22.0–35.3) for the group with normal renal function and 38.4 h (35.9–51.9) for patients with impaired renal function (P = 0.001). An influence of diabetes mellitus (Dm), renal replacement therapy or the age of the patients could not be verified. Conclusion. The results of this study clearly demonstrate that kidney function has an impact on plasma troponin concentrations. In everyday clinical practice this has to be considered when interpreting elevated plasma troponin concentration in patients with impaired renal function. [ABSTRACT FROM AUTHOR]