Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells

Receptor-PI3K-mTORC1 signaling and fatty acid synthase (FASN)-regulated lipid biosynthesis harbor numerous drug targets and are molecularly connected. We hypothesize that unraveling the mechanisms of pathway cross-talk will be useful for designing novel co-targeting strategies for ovarian cancer (OC). The impact of receptor-PI3K-mTORC1 onto FASN is already well-characterized. However, reverse actions–from FASN towards receptor-PI3K-mTORC1–are still elusive. We show that FASN-blockade impairs receptor-PI3K-mTORC1 signaling at multiple levels. Thin-layer chromatography and MALDI-MS/MS reveals that FASN-inhibitors (C75, G28UCM) augment polyunsaturated fatty acids and diminish signaling lipids diacylglycerol (DAG) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in OC cells (SKOV3, OVCAR-3, A2780, HOC-7). Western blotting and micropatterning demonstrate that FASN-blockers impair phosphorylation/expression of EGF-receptor/ERBB/HER and decrease GRB2–EGF-receptor recruitment leading to PI3K-AKT suppression. FASN-inhibitors activate stress response-genes HIF-1α-REDD1 (RTP801/DIG2/DDIT4) and AMPKα causing mTORC1- and S6-repression. We conclude that FASN-inhibitor-mediated blockade of receptor-PI3K-mTORC1 occurs due to a number of distinct but cooperating processes. Moreover, decrease of PI3K-mTORC1 abolishes cross-repression of MEK-ERK causing ERK activation. Consequently, the MEK-inhibitor selumetinib/AZD6244, in contrast to the PI3K/mTOR-inhibitor dactolisib/NVP-BEZ235, increases growth inhibition when given together with a FASN-blocker. We are the first to provide deep insight on how FASN-inhibition blocks ERBB-PI3K-mTORC1 activity at multiple molecular levels. Moreover, our data encourage therapeutic approaches using FASN-antagonists together with MEK-ERK-inhibitors

Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4′,5′-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual

Pharmacological interventions for the management of children and adolescents living with obesity – An update of a Cochrane systematic review with meta-analyses

Importance: The effectiveness of anti-obesity medications for children and adolescents is unclear. Objective: To update the evidence on the benefits and harms of anti-obesity medication. Data sources: Cochrane CENTRAL, MEDLINE, ClinicalTrials.gov, WHO ICTRP (1/1/16-17/3/23). Study selection: Randomized controlled trials ≥6-months in people <19years living with obesity. Data extraction and Synthesis: Screening, data extraction, quality assessment conducted in duplicate, independently. Main Outcomes and Measures: Body Mass Index (BMI): 95th percentile BMI, adverse events, quality of life. Results: Thirty-five trials (N=4,331), follow-up: 6-24 months; age: 8.8-16.3 years; BMI: 26.2-41.7kg/m2. Moderate certainty evidence demonstrated a -1.71 (95% confidence interval [CI]: -2.27 to -1.14)-unit BMI reduction, ranging from -0.8 to -5.9 units between individual drugs with Semaglutide producing the largest reduction of -5.88 kg/m2 (95% CI: -6.99 to -4.77, N = 201). Drug type explained ~44% of heterogeneity. Low certainty evidence demonstrated reduction in 95th percentile BMI: -11.88 percentage points (95% CI: -18.43 to -5.30, N = 668). Serious adverse events and study discontinuation due to adverse events, did not differ between medications and comparators, but medication dose adjustments were higher compared to comparator (10.6% vs 1.7%; RR = 3.74 [95% CI: 1.51 to 9.26], I2 = 15%), regardless of approval status. There was a trend towards improved quality of life. Evidence gaps exist for children, psychosocial outcomes, comorbidities, and weight loss maintenance. Conclusions and Relevance: Anti-obesity medications in addition to behaviour-change, improves BMI but may require dose adjustment, with 1 in 100 adolescents experiencing a serious adverse event

Pharmacological interventions for the management of children and adolescents living with obesity - An update of a Cochrane systematic review with meta-analyses

Importance The effectiveness of anti-obesity medications for children and adolescents is unclear. Objective To update the evidence on the benefits and harms of anti-obesity medication. Data Sources Cochrane CENTRAL, MEDLINE, ClinicalTrials.gov and WHO ICTRP (1/1/16–17/3/23). Study Selection Randomized controlled trials ≥6 months in people <19 years living with obesity. Data Extraction and Synthesis Screening, data extraction and quality assessment conducted in duplicate, independently. Main Outcomes and Measures Body mass index (BMI): 95th percentile BMI, adverse events and quality of life. Results Thirty-five trials (N = 4331), follow-up: 6–24 months; age: 8.8–16.3 years; BMI: 26.2–41.7 kg/m2. Moderate certainty evidence demonstrated a −1.71 (95% confidence interval [CI]: −2.27 to −1.14)-unit BMI reduction, ranging from −0.8 to −5.9 units between individual drugs with semaglutide producing the largest reduction of −5.88 kg/m2 (95% CI: −6.99 to −4.77, N = 201). Drug type explained ~44% of heterogeneity. Low certainty evidence demonstrated reduction in 95th percentile BMI: −11.88 percentage points (95% CI: −18.43 to −5.30, N = 668). Serious adverse events and study discontinuation due to adverse events did not differ between medications and comparators, but medication dose adjustments were higher compared to comparator (10.6% vs 1.7%; RR = 3.74 [95% CI: 1.51 to 9.26], I2 = 15%), regardless of approval status. There was a trend towards improved quality of life. Evidence gaps exist for children, psychosocial outcomes, comorbidities and weight loss maintenance. Conclusions and Relevance Anti-obesity medications in addition to behaviour change improve BMI but may require dose adjustment, with 1 in 100 adolescents experiencing a serious adverse event

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency

A potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-beta). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis. Endogenous glucose production (EGP), glycogenolysis (GGL), and gluconeogenesis (GNG) were quantified with stable isotopes in a patient with glycogen storage disease type 1a (GSD-1a) and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. The [6,6-H-2(2)]glucose dilution method in combination with the deuterated water method was used during individualized fasting tests. Both patients became hypoglycemic after 2.5 and 14.5 h fasting, respectively. At that time, the patient with GSD-1a had EGP 3.84 mu mol/kg per min (30% of normal EGP after an overnight fast), GGL 3.09 mu mol/kg per min, and GNG 0.75 mu mol/kg per min. The patient with FBPase deficiency had EGP 8.53 mu mol/kg per min (62% of normal EGP after an overnight fast), GGL 6.89 mu mol/kg per min GGL, and GNG 1.64 mu mol/kg per min. EGP was severely hampered in both patients, resulting in hypoglycemia. However, despite defective hepatic and renal GNG in both disorders and defective hepatic GGL in GSD-1a, both patients were still able to produce glucose via both pathways. As all necessary enzymes of these pathways have now been functionally detected in muscle, a contribution of muscle to EGP during fasting via both GGL as well as GNG is suggeste

Temporal resolution of protein–protein interactions in the live-cell plasma membrane

We have recently devised a method to quantify interactions between a membrane protein (“bait”) and a fluorophore-labeled protein (“prey”) directly in the live-cell plasma membrane (Schwarzenbacher et al. Nature Methods 5:1053–1060 2008). The idea is to seed cells on surfaces containing micro-patterned antibodies against the exoplasmic domain of the bait, and monitor the co-patterning of the fluorescent prey via fluorescence microscopy. Here, we characterized the time course of bait and prey micropattern formation upon seeding the cells onto the micro-biochip. Patterns were formed immediately after contact of the cells with the surface. Cells were able to migrate over the chip surface without affecting the micropattern contrast, which remained constant over hours. On single cells, bait contrast may be subject to fluctuations, indicating that the bait can be released from and recaptured on the micropatterns. We conclude that interaction studies can be performed at any time-point ranging from 5 min to several hours post seeding. Monitoring interactions with time opens up the possibility for new assays, which are briefly sketched in the discussion section

Methodology and implementation of the WHO European Childhood Obesity Surveillance Initiative (COSI)

Establishment of the WHO European Childhood Obesity Surveillance Initiative (COSI) has resulted in a surveillance system which provides regular, reliable, timely, and accurate data on children's weight status—through standardized measurement of bodyweight and height—in the WHO European Region. Additional data on dietary intake, physical activity, sedentary behavior, family background, and school environments are collected in several countries. In total, 45 countries in the European Region have participated in COSI. The first five data collection rounds, between 2007 and 2021, yielded measured anthropometric data on over 1.3 million children. In COSI, data are collected according to a common protocol, using standardized instruments and procedures. The systematic collection and analysis of these data enables intercountry comparisons and reveals differences in the prevalence of childhood thinness, overweight, normal weight, and obesity between and within populations. Furthermore, it facilitates investigation of the relationship between overweight, obesity, and potential risk or protective factors and improves the understanding of the development of overweight and obesity in European primary-school children in order to support appropriate and effective policy responses

Physical Activity, Screen Time, and Sleep Duration of Children Aged 6-9 Years in 25 Countries: An Analysis within the WHO European Childhood Obesity Surveillance Initiative (COSI) 2015-2017

Background: Children are becoming less physically active as opportunities for safe active play, recreational activities, and active transport decrease. At the same time, sedentary screen-based activities both during school and leisure time are increasing. Objectives: This study aimed to evaluate physical activity (PA), screen time, and sleep duration of girls and boys aged 6–9 years in Europe using data from the WHO European Childhood Obesity Surveillance Initiative (COSI). Method: The fourth COSI data collection round was conducted in 2015–2017, using a standardized protocol that included a family form completed by parents with specific questions about their children’s PA, screen time, and sleep duration. Results: Nationally representative data from 25 countries was included and information on the PA behaviour, screen time, and sleep duration of 150,651 children was analysed. Pooled analysis showed that: 79.4% were actively playing for >1 h each day, 53.9% were not members of a sport or dancing club, 50.0% walked or cycled to school each day, 60.2% engaged in screen time for 1 h/day, 8.2–85.6% were not members of a sport or dancing club, 17.7–94.0% walked or cycled to school each day, 32.3–80.0% engaged in screen time for <2 h/day, and 50.0–95.8% slept for 9–11 h/night. Conclusions: The prevalence of engagement in PA and the achievement of healthy screen time and sleep duration are heterogenous across the region. Policymakers and other stakeholders, including school administrators and parents, should increase opportunities for young people to participate in daily PA as well as explore solutions to address excessive screen time and short sleep duration to improve the overall physical and mental health and well-being of children.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the following countries was made possible through funding. Albania: WHO through the Joint Programme on Children, Food Security and Nutrition “Reducing Malnutrition in Children” (the Millennium Development Goals Achievement Fund) and the Institute of Public Health; Bulgaria: Ministry of Health, National Centre of Public Health and Analyses, WHO Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and WHO Regional Office for Europe; Czechia: grants AZV MZČR 17–31670 A and MZČR – RVO EÚ 00023761; Denmark: Danish Ministry of Health; Estonia: Ministry of Social Affairs, Ministry of Education and Research (IUT 42–2), WHO Country Office, and National Institute for Health Development; France: Sante Publique France, the French Agency for Public Health; Georgia: WHO; Ireland: Health Service Executive; Italy: Ministry of Health and Italian National Institute of Health; Kazakhstan: Ministry of Health of the Republic of Kazakhstan and WHO Country Office; Kyrgyzstan: WHO; Latvia: Ministry of Health, Centre for Disease Prevention and Control; Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and WHO; Malta: Ministry of Health; Montenegro: WHO and Institute of Public Health of Montenegro; Poland: National Health Programme, Ministry of Health; Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support from the Center for Studies and Research on Social Dynamics and Health (CEIDSS); Romania: Ministry of Health; San Marino: Health Ministry, Educational Ministry, Social Security Institute and Health Authority; Spain: Spanish Agency for Food Safety and Nutrition (AESAN); Turkmenistan: WHO Country Office in Turkmenistan and Ministry of Health; Turkey: Turkish Ministry of Health and the World Bank

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income&nbsp;countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of&nbsp;countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified