Die Verwertung humaner Exkremente als Ressource: Potentiale, Praxisbeispiele und politische Regulierung

In einem Webinar, das im WiSe2020/21 im Rahmen der 5. Progressiven Einführungswochen, der 7. Ökosozialen Hochschultage und des Onlineseminars „Bioökonomie“ an der OVGU Magdeburg veranstaltet wurde, referierte Herr Enno Schröder zur Nutzung von humanen Exkrementen als Ressource für die Bioökonomie. Unter dem Titel „Ab wann ist Scheiße Dünger? Bioökonomie ganz praktisch“ stellte Herr Schröder die Aktivitäten des Sozialunternehmens „Goldeimer gGmbH“ sowie des Netzwerks für Nachhaltige Sanitärsysteme e.V. (netsan.org) dar. Dabei wurden mögliche Verfahren der Kompostierung von humanen Fäkalien, potentielle Risiken sowie die aktuellen gesetzlichen Regulierung im Detail dargestellt. Aus Sicht von Goldeimer erschwert letztere eine kommerzielle Nutzung von humanen Fäkalien als eine wertvolle Ressource für die Bioökonomie. Mit einer Kombination aus wissenschaftlicher Grundlagenforschung, Standardisierung und Qualitätsicherung bei der Kompostierung, Netzwerk-Arbeit und Lobbyarbeit versuchen die Goldeimer gGmbH und Partner des Netzwerkes die Bedingungen hierfür zu verbessern. Der Bericht zu diesem Seminar wurde von Oliver Keminer verfasst und durch einige Verweise (Fussnoten) und Anmerkungen ergänzt.In a webinar organized in WiSe2020/21 as part of the 5th Progressive Introductory Weeks, the 7th Eco-social University Days and the online seminar "Bioeconomy" at OVGU Magdeburg, Mr. Enno Schröder gave a presentation on the use of human excrement as a resource for the bioeconomy. Under the titel “When does human shit become fertilizer? Bioeconomy in practice”, Mr. Schröder presented the activities of the social enterprise "Goldeimer gGmbH" and the “Netzwerk für Nachhaltige Sanitärsysteme e.V. (netsan.org)". In the talk, possible methods of composting human faeces, potential risks as well as the current legal regulation were presented in detail. From Goldeimer\u27s perspective, the latter makes it difficult to commercially utilize human feces as a valuable resource for the bioeconomy. With a combination of basic scientific research, standardization and quality assurance in composting, networking and lobbying, Goldeimer gGmbH and partners of the network try to improve the conditions for this. The report on this seminar was written by Oliver Keminer and supplemented by some references (footnotes) and comments

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 \u3bcM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 \u3bcM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion\u2013toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 (TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain

Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC):The Hot Start experience

A fast track “Hot Start” process was implemented to launch the European Bank for Induced Pluripotent Stem Cells (EBiSC) to provide early release of a range of established control and disease linked human induced pluripotent stem cell (hiPSC) lines. Established practice amongst consortium members was surveyed to arrive at harmonised and publically accessible Standard Operations Procedures (SOPs) for tissue procurement, bio-sample tracking, iPSC expansion, cryopreservation, qualification and distribution to the research community. These were implemented to create a quality managed foundational collection of lines and associated data made available for distribution. Here we report on the successful outcome of this experience and work flow for banking and facilitating access to an otherwise disparate European resource, with lessons to benefit the international research community. eTOC: The report focuses on the EBiSC experience of rapidly establishing an operational capacity to procure, bank and distribute a foundational collection of established hiPSC lines. It validates the feasibility and defines the challenges of harnessing and integrating the capability and productivity of centres across Europe using commonly available resources currently in the field

Bewertung des endokrinen Potenzials von Bisphenol Alternativstoffen in umweltrelevanten Verwendungen. Abschlussbericht

Bisphenol A (BPA) is mainly used as raw material in the production of plastic products. Due to its hormone-like effects in humans and other organisms, the use of BPA is closely connected to human health and environmental risks. Thus, there is high interest in substances with similar properties to BPA regarding its use in plastic products, however do not negatively influence the endocrine system of any organism. There are substantial data gaps regarding the molecular mode of action of many substitution candidates, which impede the assessment of their influence on the environment. A literature research was performed in order to identify environmentally relevant BPA substitution candidates. Furthermore, the interaction of these substances with a set of nuclear receptors was investigated, which might be responsible for the endocrine effects of BPA. The application of a number of biochemical and cell-based screening assays, the influence of these substances on the estrogen receptors α and β, as well as of the androgen receptor was determined

A tiered high-throughput screening approach for evaluation of estrogen and androgen receptor modulation by environmentally relevant bisphenol A substitutes

Bisphenol A (BPA) is a high production volume chemical with a broad application spectrum. As an endocrine disrupting chemical, mainly by modulation of nuclear receptors (NRs), BPA has an adverse impact on organisms and is identified as a substance of very high concern under the European REACH regulation. Various BPA substitution candidates have been developed in recent years, however, information concerning the endocrine disrupting potential of these substances is still incomplete or missing. In this study, we intended to investigate the endocrine potential of BPA substitution candidates used in environmentally relevant applications such as thermal paper or epoxy resins. Based on an extensive literature and patent search, 33 environmentally relevant BPA substitution candidates were identified. In order to evaluate the endocrine potential of the BPA replacements, a screening cascade consisting of biochemical and cell-based assays was employed to investigate substance binding to the NRs estrogen receptor α and β, as well as androgen receptor, co-activator recruitment and NR-mediated reporter gene activation. In addition, a computational docking approach for retrospective prediction of receptor binding was carried out. Our results show that some BPA substitution candidates, for which so far no or only very few data were available, possess a substantial endocrine disrupting potential (TDP, BPZ), while several substances (BPS, D-8, DD70, DMP-OH, TBSA, D4, CBDO, ISO, VITC, DPA, and DOPO) did not reveal any NR binding

Identification of Src as a Therapeutic Target in Oesophageal Adenocarcinoma through Functional Genomic and High-Throughput Drug Screening Approaches

SIMPLE SUMMARY: Oesophageal adenocarcinoma (OAC) is a leading cause of cancer mortality in the United Kingdom with a 5-year survival rate of approximately 15%. Major contributors to poor outcome are late diagnosis and chemotherapy resistance, and while targeted therapies have benefitted certain cancer settings, they have had limited success in OAC. An understanding of the mechanisms mediating chemotherapy resistance could identify novel targets with the potential to improve standard treatments. This paper aimed to identify mediators of both OAC cancer cell pro-survival signalling and chemotherapy resistance, as well as determine potential small molecular compounds to counteract this. Gene set enrichment analysis of transcriptional data generated a gene-list with significant differential expression between responder and non-responder OAC patients. Gene functionality assessment using siRNA screening showed that targeting SRC had an anti-tumour effect in OAC cells with the potential to enhance chemotherapy treatment. In parallel to this, a compound screen showed the Src inihibitor dasatinib sensitised OAC cells to chemotherapy. Together, these findings suggest targeting SRC as a novel therapeutic strategy in OAC. ABSTRACT: Drug resistance limits the effectiveness of oesophageal adenocarcinoma (OAC) chemotherapies, leading to a poor prognosis for this disease. Elucidation of the underlying resistance mechanisms is key to enabling the identification of more effective treatments. This study, therefore, aims to identify novel therapeutic and/or chemotherapy sensitising drug targets in OAC. Transcriptional data from a cohort of 273 pre-treatment OAC biopsies, from patients who received neoadjuvant chemotherapy followed by surgical resection, were analysed using gene set enrichment analysis (GSEA) to determine differential gene expression between responding and non-responding OAC tumours. From this, 80 genes were selected for high-throughput siRNA screening in OAC cell lines with or without standard chemotherapy treatment. In parallel, cell viability assays were performed using a panel of FDA-approved drugs and combination index (CI) values were calculated to evaluate drug synergy with standard chemotherapy. Mechanisms of synergy were investigated using western blot, propidium iodide flow cytometry, and proliferation assays. Taken together, the screens identified that targeting Src, using either siRNA or the small molecule inhibitor dasatinib, enhanced the efficacy of chemotherapy in OAC cells. Further in vitro functional analysis confirmed Src inhibition to be synergistic with standard OAC chemotherapies, 5-fluorouracil (5-FU), and cisplatin (CDDP). In conclusion, a compound screen together with a functional genomic approach identified Src as a potential chemosensitising target in OAC, which could be assessed in a clinical study for poor prognosis OAC patients