Auf Diäten und Fasten basierende Interventionen als neue Ansätze um die Effizienz von Krebs-Behandlungen zu steigern

Kurzzeitiges Fasten (STS) schützt normale Zellen, Mäuse und potenziell auch Patienten vor den schädlichen Nebenwirkungen einer Chemotherapie. In dieser Dissertation demonstriere ich, dass fasten-ähnliche Zellkulturkonditionen das Überleben von Nagetier- und menschlichen Krebszellen reduziert und diese gleichzeitig gegenüber chemotherapeutischen Interventionen sensitiviert. In vivo sind Fastenzyklen für manche Krebszellen ähnlich effektiv wie die verwendete Chemotherapie und reduzieren das Tumorwachstum. In Tierversuchsmodellen für Melanome, Gliome und Brustkrebs konnte die Effektivität der verwendeten Chemotherapeutika und auch Strahlentherapie in Kombination mit Fasten erhöht werden. In Mausmodellen für Neuroblastome resultierte die Chemotherapie zusammen mit Fasten in einem langzeitigen Überleben der Mäuse, während die einzelnen Therapien erfolglos blieben. In dem 4T1 Maus Brustkrebs-Modell resultierte STS in einer erhöhten Phosphorylierung der Stress sensitivierenden Kinasen AKT und S6, erhöhtem oxidativen Zellstress, Spaltung der Caspase-3, DNS-Schäden, Apoptose und der gleichzeitig reduzierten Expression von Transkriptions-Faktoren (z.B. NFkB) die eine Rolle im Widerstand gegen Zellstress spielen. Interessanterweise konnten diese Veränderungen in normalen Zellen nicht aufgefunden werden. Mehrere dieser intrazellulären Effekte stehen mit der Aktivität des Enzyms heme oxygenase-1 in Verbindung, dessen Regulierung eine zentrale Rolle in der durch das Fasten bedingten Sensitivierung von 4T1 Brustkrebs spielt. Unsere Studien deuten darauf hin, das Fasten eine differentielle Stress-Sensitivierung in einer Vielzahl von Tumoren auslösen kann, die Effektivität von Chemotherapeutika erhöhen kann und somit möglicherweise eine Alternative zu Chemotherapie darstellt. Um Alternativen zum Fasten zu finden, evaluiere ich in dieser Dissertation zusätzlich noch die Effekte von kalorienreduzierten (CR), und Nährstoff (Eiweiß, Fett und Kohlenhydrate) definierten, Nahrungsmitteln hinsichtlich ihrer Effektivität im Schutz gegen akut hohe Chemotherapie und Tumorprogression. Eine kurzzeitige 50% Reduzierung der konsumierten Kalorien, auch in Zusammenhang mit Proteindefiziten oder ketogenen Diäten, erhöhte die Resistenz gegenüber der Chemotherapie, blieb jedoch weniger effektiv als Fasten per se. Eine Diät mit hohem Proteingehalt reversierte die positiven Effekte der CR. In subkutan implantierten Gliomen blieb die Ernährung mit auf niedrigem Eiweiß basierten Kalorien (4%) in der Maus nach mehr als 20 Tagen ohne Effekt auf das bereits etablierte Tumorwachstum. Zyklen in denen die Kalorien auf 50% reduziert wurden hatten, im Gegenteil zu Fasten, keine additive Wirkung auf die Behandlung von Brustkrebszellen mit Cisplatin in der Maus. Die präsentierten Ergebnisse belegen dass Fasten, jedoch nicht kurzeitige CR oder die Modifizierung der konsumierten Nährstoffe, vor der Toxizität von Chemotherapeutika schützt und gleichzeitig Krebszellen zu einer Vielzahl von Chemotherapien sensitiviert.Short-term starvation (STS or fasting) protects normal cells, mice and potentially humans from the harmful side-effects of chemotherapeutic drugs. In this dissertation, I demonstrate that fasting-like cell culture conditions reduce cancer cell survival and sensitize human and murine cancer cell lines to chemotherapy. In vivo, cycles of STS were as effective as chemotherapeutics in delaying the progression of specific tumors and increased the effectiveness of these drugs and radiotherapy against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, STS cycles in combination with chemotherapy, but not either treatment alone, resulted in long-term cancer-free survival. In 4T1 breast cancer cells, STS led to increased phosphorylation of the stress-sensitizing AKT and S6 kinases, increased oxidative stress, caspase-3 activation, DNA damage, apoptosis, and reduced expression of the stress resistance transcription factor NFkB; all changes were not observed in normal tissues. Several of these effects are linked to the activity of the stress-responsive enzyme heme oxygenase-1, whose modulation was central in regulating chemotherapy-dependent cell death in breast cancer cells. These studies suggest that multiple cycles of STS promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of some toxic chemotherapy drugs in the treatment of various cancers. In addition, we evaluated the contribution of calorie restricted (CR) diets and defined macronutrient (carbohydrate, protein, fat) ratios for their effects on stress sensitization markers and protection in mice treated with high-dose chemotherapy. Short-term 50% CR, combined with either severe protein-deficient or ketogenic diets, improved chemotoxicity resistance similarly to the standard 50% CR, but did not result in the high protection caused by STS. Notably, a high protein diet reversed the beneficial effects of short-term CR. In a subcutaneous mouse model of glioma, feeding a low protein diet (4% calories from protein vs. 18% in the control) for more than 20 days did not delay tumor progression once the tumor became palpable. Also, cycles of short-term (3 days) 50% CR did not augment the chemotherapy efficacy of cisplatin in a murine breast cancer model. These results indicate that the protection from chemotoxicity and retardation of tumor progression achieved with fasting could not be obtained with short-term calorie and/or macronutrient restriction

Personalized Nutrition: Translating the Science of NutriGenomics Into Practice: Proceedings From the 2018 American College of Nutrition Meeting

Adverse reactions to foods and adverse drug reactions are inherent in product defects, medication errors, and differences in individual drug exposure. Pharmacogenetics is the study of genetic causes of individual variations in drug response and pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. The similarity of nutritional genomics and pharmacogenomics stems from the innate goal to identify genetic variants associated with metabolism and disease. Thus, nutrigenomics can be thought of as encompassing gene–diet interactions involving diverse compounds that are present in even the simplest foods. The advances in the knowledge base of the complex interactions among genotype, diet, lifestyle, and environment is the cornerstone that continues to elicit changes in current medical practice to ultimately yield personalized nutrition recommendations for health and risk assessment. This information could be used to understand how foods and dietary supplements uniquely affect the health of individuals and, hence, wellness. The individual’s gut microbiota is not only paramount but pivotal in embracing the multiple-functional relationships with complex metabolic mechanisms involved in maintaining cellular homeostasis. The genetic revolution has ushered in an exciting era, one in which many new opportunities are expected for nutrition professionals with expertise in nutritional genomics. The American College of Nutrition’s conference focused on “Personalized Nutrition: Translating the Science of NutriGenomics Into Practice” was designed to help to provide the education needed for the professional engagement of providers in the personalized medicine era.https://doi.org/10.1080/07315724.2019.158298

De novo assembly of a transcriptome from the eggs and early embryos of Astropecten aranciacus

Starfish have been instrumental in many fields of biological and ecological research. Oocytes of Astropecten aranciacus, a common species native to the Mediterranean Sea and the East Atlantic, have long been used as an experimental model to study meiotic maturation, fertilization, intracellular Ca2+ signaling, and cell cycle controls. However, investigation of the underlying molecular mechanisms has often been hampered by the overall lack of DNA or protein sequences for the species. In this study, we have assembled a transcriptome for this species from the oocytes, eggs, zygotes, and early embryos, which are known to have the highest RNA sequence complexity. Annotation of the transcriptome identified over 32,000 transcripts including the ones that encode 13 distinct cyclins and as many cyclin-dependent kinases (CDK), as well as the expected components of intracellular Ca2+ signaling toolkit. Although the mRNAs of cyclin and CDK families did not undergo significant abundance changes through the stages from oocyte to early embryo, as judged by real-time PCR, the transcript encoding Mos, a negative regulator of mitotic cell cycle, was drastically reduced during the period of rapid cleavages. Molecular phylogenetic analysis using the homologous amino acid sequences of cytochrome oxidase subunit I from A. aranciacus and 30 other starfish species indicated that Paxillosida, to which A. aranciacus belongs, is not likely to be the most basal order in Asteroidea. Taken together, the first transcriptome we assembled in this species is expected to enable us to perform comparative studies and to design gene-specific molecular tools with which to tackle long-standing biological questions

When the Tension Is Rising: A Simulation-Based Study on the Effects of Safety Incentive Programs and Behavior-Based Safety Management

When an organization’s management creates a goal conflict between workplace safety and the profitability of the organization, workers perceive work-safety tension. This leads to reduced safety-related behavior, culminating in higher rates of occupational injuries. In this study, we explored design components of behavior-based safety programs: audit results and process communication, reward and punishment, and the framing of production goals as gains or losses. This allowed us to directly observe the effects of the goal conflicts and of the countermeasures that we designed in this study. We examined the perceived work-safety tension using a simulated water treatment plant in a laboratory study with 166 engineering students. Participants had the task of conducting a start-up procedure. The operators’ goal conflict was created by a choice between a safe and mandatory (less productive) procedure and an unsafe and forbidden (more productive) one. As participants were told that their payment for the study would depend on their performance, we expected that rule violations would occur. We found acceptance of measures and their design as important for rule related behavior. Work-safety tension emerged as a strong driver for violating safety rules. We conclude that safety incentive programs can become ineffective if goal conflicts create work-safety tension

When the Tension Is Rising: A Simulation-Based Study on the Effects of Safety Incentive Programs and Behavior-Based Safety Management

When an organization’s management creates a goal conflict between workplace safety and the profitability of the organization, workers perceive work-safety tension. This leads to reduced safety-related behavior, culminating in higher rates of occupational injuries. In this study, we explored design components of behavior-based safety programs: audit results and process communication, reward and punishment, and the framing of production goals as gains or losses. This allowed us to directly observe the effects of the goal conflicts and of the countermeasures that we designed in this study. We examined the perceived work-safety tension using a simulated water treatment plant in a laboratory study with 166 engineering students. Participants had the task of conducting a start-up procedure. The operators’ goal conflict was created by a choice between a safe and mandatory (less productive) procedure and an unsafe and forbidden (more productive) one. As participants were told that their payment for the study would depend on their performance, we expected that rule violations would occur. We found acceptance of measures and their design as important for rule related behavior. Work-safety tension emerged as a strong driver for violating safety rules. We conclude that safety incentive programs can become ineffective if goal conflicts create work-safety tension

Regelbezogenes Sicherheitsverhalten im Spannungsfeld organisationskultureller Facetten

Die Dissertation untersucht verhältnisbezogene Faktoren und ihr Einfluss auf regelbezogenes Verhalten in High-Reliability Organizations. Es wurden vier Forschungsschwerpunkte gewählt: 1) Handlungskonsequenzen, 2) Feedbackkommunikation, 3) Zielkonflikte sowie 4) Vergütungsmodelle. Basierend auf den Ergebnissen wird ein Modell angenommen, in dem Gerechtigkeits- und Fehlerkultur die Basis bilden, auf der Kommunikations- und Berichtskultur aufbauen, um die Sicherheitskultur zu unterstützen. Interaktionseffekte zeigen, dass verschiedene Facetten der Organisationskultur sich gegenseitig beeinflussen und den beabsichtigten sicherheitsfördernden Effekt von BBSM-Maßnahmen umkehren können. Die Korrelationen zwischen personenbezogenen Variablen und Regelabweichungen betonen die Bedeutung der Gerechtigkeitskultur. Zukünftige Arbeiten sollten das Modell konkretisieren und empirisch überprüfen, sowie motivationsbezogene Aspekte integrieren

Incentive Schemes Increase Risky Behavior in a Safety-Critical Working Task: An Experimental Comparison in a Simulated High-Reliability Organization

As financial incentive schemes have the tendency to increase risky behavior, we analyzed their effect on rule-related behavior in a safety-critical task. We compared risky behavior (in terms of the amount of rule violations) between three payment condition: continuous, up-front, and bonus pay. Fifty-nine participants were trained as production personnel to conduct a start-up procedure of a simulated wastewater treatment plant, representing a high reliability organization. During the 5-h experimental study, risky behavior could have been applied 48 times while building a simulated production year. The results show that the conditions with an incentive scheme (up-front and bonus pay) led to significantly more rule violations than the condition with continuous payment without an incentive scheme. Our study highlights the general increased risk effect of incentive schemes and provides a starting point for industries to assess their implicit and explicit incentive schemes

Unintended Detrimental Effects of the Combination of Several Safety Measures—When More Is Not Always More Effective

To ensure safety-related behavior in risky operations, several safety measures, such as safety-related rules and safety management systems including audits, rewards, and communication, are implemented. Looking at each single measure, it is reasonable to assume that each one leads to rule compliance, but how do they interact? In an experimental study, we varied (1) the salience of either safety, productivity, or both, (2) the reward for the compliance and punishment for a violation, (3) the communication of audit results (result- or process-based), and (4) the gain and loss framing of performance indicators. In a 3 × 2 × 2 × 2 factorial between-group design, 497 engineering students in the role of Control Room Operator participated in a five hour simulation of a production year of a chemical plant. Looking at single effects, salient safety goals led to a low number of rule violations compared to the salience of production goals. Interestingly, the interaction of several measures showed that particular combinations of measures were highly detrimental to safety, although altogether, they were assumed to reduce risks. For practice, this means that the effects of safety measures depend on their particular combination and can lead to unwanted effects

Incentive Schemes Increase Risky Behavior in a Safety-Critical Working Task: An Experimental Comparison in a Simulated High-Reliability Organization

As financial incentive schemes have the tendency to increase risky behavior, we analyzed their effect on rule-related behavior in a safety-critical task. We compared risky behavior (in terms of the amount of rule violations) between three payment condition: continuous, up-front, and bonus pay. Fifty-nine participants were trained as production personnel to conduct a start-up procedure of a simulated wastewater treatment plant, representing a high reliability organization. During the 5-h experimental study, risky behavior could have been applied 48 times while building a simulated production year. The results show that the conditions with an incentive scheme (up-front and bonus pay) led to significantly more rule violations than the condition with continuous payment without an incentive scheme. Our study highlights the general increased risk effect of incentive schemes and provides a starting point for industries to assess their implicit and explicit incentive schemes

The Effects of Dietary Interventions on Brain Aging and Neurological Diseases

Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases