[Opportunities and challenges of active patient involvement in clinical research in Germany - from the perspectives of a patient representative, a clinical researcher and two staff members of research funding management]. / Chancen und Herausforderungen der aktiven Beteiligung von Patient*innen an klinischer Forschung in Deutschland ­ Eine Betrachtung aus den Perspektiven eines Patient*innenvertreters, einer klinischen Forscherin und zweier Mitarbeiterinnen des Forschungsfördermanagements.

BACKGROUND: Active involvement of patients in clinical research is increasingly demanded in Germany. It has great potential to increase the quality and relevance of research and to contribute to patient empowerment. However, patients, researchers and research funders have experienced that the implementation of patient involvement is accompanied by cultural, practical and personal challenges. The aim of this article is to discuss the opportunities and challenges of patient involvement in Germany from the perspective of the stakeholders involved. METHOD: A patient representative, a clinical researcher and two staff members from research funding management were invited to discuss the opportunities and challenges of patient involvement. Their perspectives were recorded in two written open survey rounds. The answers were analyzed using qualitative content analysis. RESULT: In the opinion of the stakeholders involved, the increasing involvement of patients in clinical research is an opportunity to promote the practical relevance of research and the implementation of studies, to increase their acceptance by the target group and to improve the uptake of research results in practice. However, the implementation of patient involvement was also perceived as challenging. They described problems with regard to the acquisition and selection of patients, the training of the patients and the specifications and support structures for the implementation of patient involvement. DISCUSSION: While patient involvement in clinical research offers great potential, the development of appropriate structures and framework conditions for its implementation is still virtually unestablished in Germany. This needs to include, among other things, creating a broader awareness of the potential of patient involvement, developing training programs for patients and researchers, providing sufficient, mainly project-independent resources and ensuring regular evaluations.

Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo.

OBJECTIVE: Single-nucleotide polymorphisms in the FTO gene encoding an m6Am and an m6A demethylase are associated with obesity. Moreover, recent studies have linked a dysregulation of m6A modifications and its machinery, including FTO, to the development of several forms of cancers. However, the functional role of hepatic FTO in metabolism and the development and progression of hepatocellular carcinoma (HCC), a proteotypic obesity-associated cancer, remains unclear. Thus, we aimed to reveal the role of hepatic FTO in metabolism and in the initiation and progression of HCC in vivo. METHODS: We generated mice with hepatic FTO deficiency (FTOL-KO). The effect of hepatic FTO on metabolism was investigated by extensive metabolic phenotyping. To determine the impact of hepatic FTO on HCC development, FTOL-KO and Ctrl mice were subjected to long-term diethylnitrosamine (DEN)-induced HCC-development and the tumor initiation phase was examined via a short-term DEN protocol. RESULTS: In long-term DEN experiments, FTOL-KO mice exhibit increased HCC burden compared to Ctrl mice. In the tumor initiation phase, Ctrl mice display a dynamic regulation of FTO upon induction of liver damage, while this response is abrogated in FTO-deficient mice. Proteomic analyses revealed that liver damage-induced increases in FTO expression reduce CUL4A protein abundance. Functionally, simultaneous knockdown of Cul4a reverses the increased hepatocyte proliferation observed upon loss of FTO. CONCLUSION: Collectively, our study demonstrates that hepatic FTO is dispensable for the control of energy homeostasis and glucose metabolism. However, we show a protective function of FTO in liver carcinogenesis and suggest the FTO-dependent dynamic mRNA demethylation of Cul4a in the initiation of HCC development contributes to this effect.

Impaired neonatal survival of pro-opiomelanocortin null mutants.

Intercrosses of heterozygous pro-opiomelanocortin (POMC) mice result in homozygous null progeny at lower frequencies than expected. Genotyping offspring at pre-, peri-, and postnatal stages revealed that over half of homozygous null mutants die in the early postnatal stages. To investigate the reasons for this early postnatal lethality, we analyzed in detail different parameters in the initial hours after birth. POMC null mutants born to heterozygous dams presented at birth with corticosterone levels no different from wildtype littermates, were euglycemic, and had normal liver glycogen stores. However, already 30 min after birth corticosterone levels dropped by 80% and were undetectable thereafter, while corticosterone levels in wildtype animals increased during postnatal hours. Circulating adrenaline was almost below detection 1h after birth. Blood glucose levels fell sharply in all genotypes within 30 min after birth; however, wildtype and heterozygous pups overcame hypoglycemia within an hour, while mutant pups stayed hypoglycemic. The depletion of liver glycogen stores in mutant pups was significantly less efficient compared to their littermates in the hours after birth. POMC null mutant mice born to POMC null mutant dams completely lack corticosterone and die of the expected respiratory dysfunction. In contrast, POMC null mutant mice born to heterozygous dams do not die of respiratory problems, but rather due to hypoglycemia. Our studies confirm an essential involvement of POMC peptides and of adrenal glucocorticoids and catecholamines on glucose homeostasis critical for early postnatal survival.