TY - THES A1 - Thierbach, René T1 - Identifikation des mitochondrialen Proteins Frataxin als stoffwechselmodulierenden Tumorsuppressor N2 - Die Krebsentstehung wurde vor rund 80 Jahren auf veränderten zellulären Energiestoffwechsel zurückgeführt. Diese Hypothese konnte bisher weder experimentell bewiesen noch widerlegt werden. Durch den Einsatz zweier Modellsysteme mit unterschiedlicher Expression des mitochondrialen Proteins Frataxin konnte in der vorliegenden Arbeit gezeigt werden, dass der mitochondriale Energiestoffwechsel einen Einfluss auf die Tumorentstehung zu besitzen scheint. Eine Reduktion des mitochondrialen Energiestoffwechsels wurde durch die hepatozytenspezifische Ausschaltung des mitochondrialen Proteins Frataxin in Mäusen erreicht. Der durch das Cre-/loxP-Rekombinasesystem erreichte organspezifische Knock-out wurde auf Transkriptions- und Translationsebene nachgewiesen. Anhand verminderter Aconitaseaktivität, geringeren Sauerstoffverbrauches und reduzierten ATP-Gehaltes im Lebergewebe wurde ein signifikant verminderter Energiestoffwechsel dargestellt. Zwar entsprach die Genotypenverteilung in den Versuchsgruppen der erwarteten Mendelschen Verteilung, dennoch war die mittlere Lebenserwartung der Knock-out-Tiere mit ca. 30 Wochen stark reduziert. Bereits in jungem Alter war bei diesen Tieren die Ausbildung von präneoplastischen Herden zu beobachten. Mit proteinbiochemischen Nachweistechniken konnte in Lebergewebe 4-8 Wochen alter Tiere eine verstärkte Aktivierung des Apoptosesignalweges (Cytochrom C im Zytosol, verstärkte Expression von Bax) sowie eine Modulation stressassoziierter Proteine (geringere Phosphorylierungsrate p38-MAPK, vermehrte Expression HSP-25, verminderte Expression HSP-70) aufgezeigt werden. Im inversen Ansatz wurde eine Steigerung des mitochondrialen Energiestoffwechsels durch stabile transgene Frataxinüberexpression in zwei Kolonkarzinomzelllinien erreicht. Diese Steigerung zeigte sich durch erhöhte Aconitaseaktivität, erhöhten Sauerstoffverbrauch, gesteigertes mitochondriales Membranpotenzial und erhöhten ATP-Gehalt in den Zellen. Die frataxinüberexprimierenden Zellen wuchsen signifikant langsamer als Kontrollzellen und zeigten im Soft-Agar-Assay und im Nacktmausmodell ein deutlich geringeres Potenzial zur Ausbildung von Kolonien bzw. Tumoren. Mittels Immunoblot war hier eine vermehrte Phosphorylierung der p38-MAPK festzustellen. Die zusammenfassende Betrachtung beider Modelle zeigt, dass ein reduzierter mitochondrialer Energiestoffwechsel durch Regulation der p38-MAPK und apoptotischer Signalwege ein erhöhtes Krebsrisiko zu verursachen vermag. N2 - Eigthy years ago, it was suggested that impaired energy metabolism might cause cancer. Compelling experimental evidence for this hypothesis is lacking. By use of two different model systems here we show that impaired expression of the mitochondrial protein frataxin leading to impaired mitochondrial energy metabolism appears to be inversely related to tumour growth. To generate mice with reduced mitochondrial energy metabolism the expression of mitochondrial protein frataxin was disrupted in a hepatocyte-specific manner by using the cre/loxP-system. Presence, efficiency and specificity of disruption were shown at transcriptional and translational levels. Decreased activity of aconitase, reduced oxygen consumption and diminished ATP level in the liver revealed diminished energy metabolism. Although knock-out mice were born in the expected Mendelian frequency, they exhibited a significantly decreased life expectancy. Young mice exhibited hepatic preneoplasia. The use of proteinbiochemical techniques revealed activation of apoptotic pathways (cytochrome c in the cytosol, increased expression of bax) and modulation of stress-associated cascades (decreased phosphorylation of p38-MAPK, increased expression of HSP-25 and diminished expression of HSP-70). Inversely, transgenic overexpression of frataxin in colon cancer cell lines lead to increased mitochondrial energy metabolism as demonstrated by elevated activity of aconitase, increased oxygen consumption, elevated mitochondrial membrane potential and increased ATP levels. Frataxin-overexpressing colon cancer cells exhibit a concurrent decrease in replication rate. The colony forming capacity in soft-agar-assay and tumour formation in nude mice were clearly decreased. Immunoblotting revealed elevated phosphorylation of p38-MAPK. Taken together, these models suggest that reduced mitochondrial energy metabolism may promote cancer through regulation of p38-MAPK and apoptotic pathways. T2 - Identifikation des mitochondrialen Proteins Frataxin als stoffwechselmodulierenden Tumorsuppressor KW - Energiestoffwechsel KW - Krebs KW - Frataxin KW - Knock-out KW - Zelllinien KW - Tumor KW - Mitochondrien KW - metabolism KW - cancer KW - frataxin KW - knock-out KW - cell line KW - tumor KW - energy KW - mitochondria Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-0001943 ER - TY - JOUR A1 - Galbete, Cecilia A1 - Kröger, Janine A1 - Jannasch, Franziska A1 - Iqbal, Khalid A1 - Schwingshackl, Lukas A1 - Schwedhelm, Carolina A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Schulze, Matthias Bernd T1 - Nordic diet, Mediterranean diet, and the risk of chronic diseases BT - the EPIC-Potsdam study JF - BMC Medicine N2 - Background: The Mediterranean Diet (MedDiet) has been acknowledged as a healthy diet. However, its relation with risk of major chronic diseases in non-Mediterranean countries is inconclusive. The Nordic diet is proposed as an alternative across Northern Europe, although its associations with the risk of chronic diseases remain controversial. We aimed to investigate the association between the Nordic diet and the MedDiet with the risk of chronic disease (type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer) in the EPIC-Potsdam cohort. Methods: The EPIC-Potsdam cohort recruited 27,548 participants between 1994 and 1998. After exclusion of prevalent cases, we evaluated baseline adherence to a score reflecting the Nordic diet and two MedDiet scores (tMDS, reflecting the traditional MedDiet score, and the MedPyr score, reflecting the MedDiet Pyramid). Cox regression models were applied to examine the association between the diet scores and the incidence of major chronic diseases. Results: During a follow-up of 10.6 years, 1376 cases of T2D, 312 of MI, 321 of stroke, and 1618 of cancer were identified. The Nordic diet showed a statistically non-significant inverse association with incidence of MI in the overall population and of stroke in men. Adherence to the MedDiet was associated with lower incidence of T2D (HR per 1 SD 0.93, 95% CI 0.88-0.98 for the tMDS score and 0.92, 0.87-0.97 for the MedPyr score). In women, the MedPyr score was also inversely associated with MI. No association was observed for any of the scores with cancer. Conclusions: In the EPIC-Potsdam cohort, the Nordic diet showed a possible beneficial effect on MI in the overall population and for stroke in men, while both scores reflecting the MedDiet conferred lower risk of T2D in the overall population and of MI in women. KW - Mediterranean diet KW - Nordic diet KW - regional diets KW - chronic diseases KW - diabetes KW - myocardial infarction KW - stroke KW - cancer KW - EPIC-Potsdam study KW - longitudinal analysis Y1 - 2018 U6 - https://doi.org/10.1186/s12916-018-1082-y SN - 1741-7015 VL - 16 PB - BMC CY - London ER - TY - JOUR A1 - Li, Chen A1 - Stoma, Svetlana A1 - Lotta, Luca A. A1 - Warner, Sophie A1 - Albrecht, Eva A1 - Allione, Alessandra A1 - Arp, Pascal P. A1 - Broer, Linda A1 - Buxton, Jessica L. A1 - Boeing, Heiner A1 - Langenberg, Claudia A1 - Codd, Veryan T1 - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length JF - American Journal of Human Genetics N2 - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. KW - Mendelian randomization KW - risk KW - variants KW - disease KW - cancer KW - loci KW - database KW - genes KW - heart KW - gwas Y1 - 2019 VL - 106 IS - 3 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Christakoudi, Sofa A1 - Tsilidis, Konstantinos K. A1 - Muller, David C. A1 - Freisling, Heinz A1 - Weiderpass, Elisabete A1 - Overvad, Kim A1 - Söderberg, Stefan A1 - Häggström, Christel A1 - Pischon, Tobias A1 - Dahm, Christina C. A1 - Zhang, Jie A1 - Tjønneland, Anne A1 - Schulze, Matthias Bernd T1 - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort JF - Scientific Reports N2 - Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring. KW - all-cause mortality KW - anthropometric measures KW - mass index KW - overweight KW - cancer KW - prediction KW - adiposity KW - size Y1 - 2020 VL - 10 IS - 1 PB - Springer Nature CY - Berlin ER - TY - GEN A1 - Li, Chen A1 - Stoma, Svetlana A1 - Lotta, Luca A. A1 - Warner, Sophie A1 - Albrecht, Eva A1 - Allione, Alessandra A1 - Arp, Pascal P. A1 - Broer, Linda A1 - Buxton, Jessica L. A1 - Boeing, Heiner A1 - Langenberg, Claudia A1 - Codd, Veryan T1 - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1205 KW - Mendelian randomization KW - risk KW - variants KW - disease KW - cancer KW - loci KW - database KW - genes KW - heart KW - gwas Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-526843 SN - 1866-8372 IS - 3 ER - TY - GEN A1 - Christakoudi, Sofa A1 - Tsilidis, Konstantinos K. A1 - Muller, David C. A1 - Freisling, Heinz A1 - Weiderpass, Elisabete A1 - Overvad, Kim A1 - Söderberg, Stefan A1 - Häggström, Christel A1 - Pischon, Tobias A1 - Dahm, Christina C. A1 - Zhang, Jie A1 - Tjønneland, Anne A1 - Schulze, Matthias Bernd T1 - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1200 KW - all-cause mortality KW - anthropometric measures KW - mass index KW - overweight KW - cancer KW - prediction KW - adiposity KW - size Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-525827 SN - 1866-8372 IS - 1 ER - TY - GEN A1 - Haß, Ulrike A1 - Herpich, Catrin A1 - Norman, Kristina T1 - Anti-Inflammatory Diets and Fatigue T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals’ use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 803 KW - chronic fatigue KW - cancer KW - fatigue reduction diet KW - probiotics KW - polyphenols KW - omega-3 fatty acids KW - anti-inflammatory nutrition KW - cytokines KW - inflammation KW - myalgic encephalomyelitis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441172 SN - 1866-8372 IS - 803 ER - TY - JOUR A1 - Haß, Ulrike A1 - Herpich, Catrin A1 - Norman, Kristina T1 - Anti-Inflammatory Diets and Fatigue JF - Nutrients N2 - Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals’ use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue. KW - chronic fatigue KW - cancer KW - fatigue reduction diet KW - probiotics KW - polyphenols KW - omega-3 fatty acids KW - anti-inflammatory nutrition KW - cytokines KW - inflammation KW - myalgic encephalomyelitis Y1 - 2019 U6 - https://doi.org/10.3390/nu11102315 SN - 2072-6643 VL - 11 IS - 10 PB - MDPI CY - Basel ER - TY - JOUR A1 - Jannasch, Franziska A1 - Nickel, Daniela V. A1 - Bergmann, Manuela M. A1 - Schulze, Matthias Bernd T1 - A new evidence-based diet score to capture associations of food consumption and chronic disease risk JF - Nutrients / Molecular Diversity Preservation International (MDPI) N2 - Previously, the attempt to compile German dietary guidelines into a diet score was predominantly not successful with regards to preventing chronic diseases in the EPIC-Potsdam study. Current guidelines were supplemented by the latest evidence from systematic reviews and expert papers published between 2010 and 2020 on the prevention potential of food groups on chronic diseases such as type 2 diabetes, cardiovascular diseases and cancer. A diet score was developed by scoring the food groups according to a recommended low, moderate or high intake. The relative validity and reliability of the diet score, assessed by a food frequency questionnaire, was investigated. The consideration of current evidence resulted in 10 key food groups being preventive of the chronic diseases of interest. They served as components in the diet score and were scored from 0 to 1 point, depending on their recommended intake, resulting in a maximum of 10 points. Both the reliability (r = 0.53) and relative validity (r = 0.43) were deemed sufficient to consider the diet score as a stable construct in future investigations. This new diet score can be a promising tool to investigate dietary intake in etiological research by concentrating on 10 key dietary determinants with evidence-based prevention potential for chronic diseases. KW - diet score KW - dietary guidelines KW - food groups KW - chronic disease KW - type 2 KW - diabetes KW - cardiovascular disease KW - cancer KW - prevention KW - reliability; KW - validity Y1 - 2022 U6 - https://doi.org/10.3390/nu14112359 SN - 2072-6643 VL - 14 IS - 11 PB - MDPI CY - Basel ER - TY - JOUR A1 - Christakoudi, Sofia A1 - Pagoni, Panagiota A1 - Ferrari, Pietro A1 - Cross, Amanda J. A1 - Tzoulaki, Ioanna A1 - Muller, David C. A1 - Weiderpass, Elisabete A1 - Freisling, Heinz A1 - Murphy, Neil A1 - Dossus, Laure A1 - Turzanski Fortner, Renee A1 - Agudo, Antonio A1 - Overvad, Kim A1 - Perez-Cornago, Aurora A1 - Key, Timothy J. A1 - Brennan, Paul A1 - Johansson, Mattias A1 - Tjonneland, Anne A1 - Halkjaer, Jytte A1 - Boutron-Ruault, Marie-Christine A1 - Artaud, Fanny A1 - Severi, Gianluca A1 - Kaaks, Rudolf A1 - Schulze, Matthias B. A1 - Bergmann, Manuela M. A1 - Masala, Giovanna A1 - Grioni, Sara A1 - Simeon, Vittorio A1 - Tumino, Rosario A1 - Sacerdote, Carlotta A1 - Skeie, Guri A1 - Rylander, Charlotta A1 - Borch, Kristin Benjaminsen A1 - Quiros, J. Ramon A1 - Rodriguez-Barranco, Miguel A1 - Chirlaque, Maria-Dolores A1 - Ardanaz, Eva A1 - Amiano, Pilar A1 - Drake, Isabel A1 - Stocks, Tanja A1 - Häggström, Christel A1 - Harlid, Sophia A1 - Ellingjord-Dale, Merete A1 - Riboli, Elio A1 - Tsilidis, Konstantinos K. T1 - Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort JF - International journal of cancer N2 - Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (+/- 0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood. KW - BMI change KW - cancer KW - middle adulthood KW - weight gain KW - weight loss Y1 - 2020 U6 - https://doi.org/10.1002/ijc.33339 SN - 0020-7136 SN - 1097-0215 VL - 148 IS - 7 SP - 1637 EP - 1651 PB - Wiley CY - Hoboken ER -