Correction: Competitive Mirror Image Phage Display Derived Peptide Modulates Amyloid Beta Aggregation and Toxicity.

[This corrects the article DOI: 10.1371/journal.pone.0147470.].

Competitive Mirror Image Phage Display Derived Peptide Modulates Amyloid Beta Aggregation and Toxicity.

Alzheimer´s disease is the most prominent type of dementia and currently no causative treatment is available. According to recent studies, oligomeric species of the amyloid beta (Aß) peptide appear to be the most toxic Aß assemblies. Aß monomers, however, may be not toxic per se and may even have a neuroprotective role. Here we describe a competitive mirror image phage display procedure that allowed us to identify preferentially Aß1-42 monomer binding and thereby stabilizing peptides, which destabilize and thereby eliminate toxic oligomer species. One of the peptides, called Mosd1 (monomer specific d-peptide 1), was characterized in more detail. Mosd1 abolished oligomers from a mixture of Aß1-42 species, reduced Aß1-42 toxicity in cell culture, and restored the physiological phenotype in neuronal cells stably transfected with the gene coding for human amyloid precursor protein.

Graph-Based Design Languages: A Lingua Franca for Product Design Including Abstract Geometry.

Product engineering involves designing and dimensioning a product, including geometric modeling and scientific simulation and analysis to fulfill predetermined requirements. Therefore, the engineering design effort requires a multidisciplinary analysis that is based on a multitude of different models, each of which require a different kind of representation of the same product geometry. The proposed approach uses a design language and a design compiler to translate an abstract source geometry in an abstract representation scheme into an arbitrary target format. With this approach, all models are generated automatically and are consistent with each other.

QIAD assay for quantitating a compound's efficacy in elimination of toxic Aß oligomers.

Strong evidence exists for a central role of amyloid ß-protein (Aß) oligomers in the pathogenesis of Alzheimer's disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aß aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAß3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aß aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease.

Preclinical evaluation of oncolytic vaccinia virus for therapy of canine soft tissue sarcoma.

Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS.

Significant Growth Inhibition of Canine Mammary Carcinoma Xenografts following Treatment with Oncolytic Vaccinia Virus GLV-1h68.

Canine mammary carcinoma is a highly metastatic tumor that is poorly responsive to available treatment. Therefore, there is an urgent need to identify novel agents for therapy of this disease. Recently, we reported that the oncolytic vaccinia virus GLV-1h68 could be a useful tool for therapy of canine mammary adenoma in vivo. In this study we analyzed the therapeutic effect of GLV-1h68 against canine mammary carcinoma. Cell culture data demonstrated that GLV-1h68 efficiently infected and destroyed cells of the mammary carcinoma cell line MTH52c. Furthermore, after systemic administration, this attenuated vaccinia virus strain primarily replicated in canine tumor xenografts in nude mice. Finally, infection with GLV-1h68 led to strong inflammatory and oncolytic effects resulting in significant growth inhibition of the tumors. In summary, the data showed that the GLV-1h68 virus strain has promising potential for effective treatment of canine mammary carcinoma.

Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas.

PURPOSE: The prognosis of patients with biliary tree carcinomas is very poor. The diagnosis often occurs at an advanced stage, when curative resection is not possible. We combined gemcitabine and docetaxel to optimize the palliative therapy for patients with gallbladder, biliary, and cholangio-carcinomas on an outpatient basis. PATIENTS AND METHODS: Patients with histologically proven biliary tree carcinomas and a WHO performance status <2 received gemcitabine 1000 mg/m2 followed by docetaxel 35 mg/m2 weekly for 3 weeks followed by I week of rest. RESULTS: Forty-three patients, 14 males/29 females, with an average age of 63.3 years (range, 41 to 78) have been enrolled since 1998; 37 have completed treatment. So far, 168 cycles (range, 1 to 16) have been administered. All 43 patients were included in the response and toxicity assessments. There are no complete remissions; however, 4 (9.3%) patients achieved partial remission, 1 (2.3%) had a minimal remission, and 24 (55.8%) reached disease stabilization for a median period of 5.2 months. Fourteen (32.6%) patients progressed. The median overall survival rate is currently 11.0 months. Grade 3 hematologic toxicities were infrequent, and there were no grade 4 hematologic toxicities. Grade 3 leukopenia was reported in 4 (9.3%) patients, grade 3 thrombozytopenia in 1 (2.3%) patient, and grade 3 anemia in 1 (2.3%) patient. Twenty-eight (65.1%) patients had grade 3/4 alopecia, 8 (18.6%) had nausea/vomiting, and 2 (4.6%) had mucositis. CONCLUSION: The combination of gemcitabine/docetaxel is an effective and well tolerated therapy for patients with advanced or metastatic gallbladder, biliary, and cholangio-carcinomas.