SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of ...epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16
-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
Polycystic Ovary Syndrome (PCOS) is a very common endocrine disorder with a variety of symptoms. Current treatment options include the contraceptive pill as well as metformin, however both treatments ...are limited to specific symptoms and have common side effects.
This phase IV study is a monocentric, double blinded randomized clinical trial comparing the effects of six months of probiotic intervention to a placebo, with an additional open-label metformin arm as a positive control in a total of 180 participants with PCOS. The first of three visits is the screening visit, where inclusion/exclusion criteria are assessed. At the first visit, they are randomised into one of the three treatment arms equally and receive their study medication. After six months, all assessments from the first two visits are repeated. The primary endpoint is the change in free testosterone levels after the intervention, while secondary endpoints include changes in hormonal and metabolic parameters associated with PCOS as well as the gut microbial composition and diversity after intervention.
Based on new insights into the role of the gut microbiome in PCOS development, this study is exploring the potential of using probiotics to treat women with PCOS symptoms. If successful, this new therapy approach could open a new realm of possibilities for treating PCOS. To our knowledge, this is the first study comparing probiotic intervention with not only placebo treatment, but also metformin. This study has been approved by the ethics committee of the Medical University of Graz (EC number 32-230 ex 19/20).
EudraCT number: 2020-000228-20.
gov identifier: NCT04593459.
Version 1.5 dated 29th November 2021.
Side effects due to allergic reactions to vaccine antigen or to additives such as chicken protein or gelatin have been known for some time. Recent findings regarding reactions mediated via the ...carbohydrate epitope galactose-alpha-1,3-galactose (alpha-gal), a constituent of animal gelatin, broaden the spectrum of gelatin-related allergies. This case series presents four patients who developed anaphylactic reactions following rabies vaccination using the vaccine Rabipur®. After appropriate allergy testing by skin prick testing and the determination of specific IgE to allergens in the vaccine, triggering by alpha-gal could be excluded and an allergy to gelatin was detected. The absence of allergic symptoms following the consumption of gelatin could potentially be explained through intestinal hydrolysis resulting in a loss of allergenic potency. Further implications related to the use of gelatin-containing infusions in emergency medicine are discussed.
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study ...(ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
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•For healthy, non-obese adults, ADF is safe to practice for several months•4-week ADF decreases the body weight by 4.5% and improves the fat-to-lean ratio•Cardiovascular parameters and the CVD risk are improved upon ADF•ADF reduces T3 and periodically depletes amino acids, while increasing PUFAs
Stekovic et al. show in the clinic that alternate day fasting (ADF) is a simple alternative to calorie restriction and provokes similar improvements on cardiovascular parameters and body composition. ADF was shown to be safe and beneficial in healthy, non-obese humans, not impairing immune function or bone health.
Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR‐based genotyping of lactase ...gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis.
Introduction: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A −13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly.
Materials and Methods: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction‐based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures.
Results: Twenty‐four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age‐adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by −7% to −11% depending on the site measured (p = 0.04). LCT(T/C−13910) polymorphisms alone accounted for 2–4 % of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p = 0.001). Milk calcium intake was significantly lower (−55%, p = 0.004) and aversion to milk consumption was significantly higher (+166%, p = 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values.
Conclusion: The LCT(T/C−13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.
Background: Metabolic regulation of glucose can be altered by fasting periods. The aim of our study was to examine the glucose metabolism after an overnight fast (12 hours) as well as after prolonged ...fasting (36 hours of fasting) in non-obese people, people with obesity and people with type 2 diabetes (T2DM).
Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after 12 and 36 hours fasting, respectively. Area under the curve (AUC) was calculated according to the trapezoidal rule. Insulin sensitivity was estimated by using QUICKI and HOMA-IR.
Results: In total 60 participants (age 43±16 years, 62% women) were included. Fasting levels of glucose, insulin and c-peptide were significantly lower in all cohorts after 36 hours vs. 12 hours of fasting (p<0.05). However, in non-obese people mean 2h-glucose level was significant higher after prolonged fasting 108.7±31.1 mg/dL vs. 79.4±18.4mg/dL after 12h fasting; p<0.05 with significantly lower 30 minutes insulin levels following prolonged fasting, while within the two other cohorts no change in this 2h-glucose was observed. Indices of insulin sensitivity improved in all groups after prolonged fasting.
Conclusion: Our data demonstrate higher glucose excursions and a reduced early insulin response after 36 hours of fasting compared to an overnight fasting period in participants with various glucose tolerance levels.
Disclosure
N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Kojzar: None. C. Sourij: None. O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. B.M. Obermayer-Pietsch: None. R. Riedl: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.
Natural aquatic environments such as oceans, lakes, and rivers are home to a tremendous diversity of microorganisms. Some may cross the air-water interface within droplets and become airborne, with ...the potential to impact the Earth's radiation budget, precipitation processes, and spread of disease. Larger droplets are likely to return to the water or adjacent land, but smaller droplets may be suspended in the atmosphere for transport over long distances. Here, we report on a series of controlled laboratory experiments to quantify wind-driven droplet production from a freshwater source for low wind speeds. The rate of droplet production increased quadratically with wind speed above a critical value (10-m equivalent 5.7 m/s) where droplet production initiated. Droplet diameter and ejection speeds were fit by a gamma distribution. The droplet mass flux and momentum flux increased with wind speed. Two mechanisms of droplet production, bubble bursting and fragmentation, yielded different distributions for diameter, speed, and angle. At a wind speed of about 3.5 m/s, aqueous suspensions of the ice-nucleating bacterium
were collected at rates of 283 cells m
s
at 5 cm above the water surface, and at 14 cells m
s
at 10 cm above the water surface. At a wind speed of about 4.0 m/s, aqueous suspensions of
were collected at rates of 509 cells m
s
at 5 cm above the water surface, and at 81 cells m
s
at 10 cm above the water surface. The potential for microbial flux into the atmosphere from aquatic environments was calculated using known concentrations of bacteria in natural freshwater systems. Up to 3.1 × 10
cells m
s
of water surface were estimated to leave the water in potentially suspended droplets (diameters <100 µm). Understanding the sources and mechanisms for bacteria to aerosolize from freshwater aquatic sources may aid in designing management strategies for pathogenic bacteria, and could shed light on how bacteria are involved in mesoscale atmospheric processes.
Background: It is well known that the metabolic regulation of glucose can be influenced by dietary interventions, including alterations in meal timing. Aim of our analysis was to examine the glucose ...metabolism after an overnight fast (10 hours) and after prolonged fasting (36 hours of fasting).
Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after an overnight fasting period of 10 hours and a fasting period of 36h. Beta-cell function was quantified by 1st and 2nd phase insulin secretion indices.
Results: We included 37 healthy subjects (mean age 48±10 years; 54% women) with a mean body mass index (BMI) of 25.2±3.4 kg/m2. After prolonged fasting mean 2h-glucose and AUC for glucose value were significantly higher than after 10h fasting (2h-glucose: 110±27 mg/dL vs. 89±24 mg/dL; p<0.001) (AUCglucose: 5336±3302 mg/dL/min vs. 3692±2266 mg/dL/min; p=0.002). First (745±500 vs. 982±573; p=0.012) and second phase insulin secretion (211 ± 115 vs. 266 ± 132; p=0.011) were significantly lower after 36h of fasting as compared to an overnight fast. Estimates for insulin sensitivity are similar after 10 and 36 hours of fasting.
Conclusion: Our data demonstrate higher glucose excursions and a reduced insulin response after a 36 hour fasting period as compared to an overnight fasting period in healthy subjects.After 10h fastingAfter 36h fastingp-valueFasting c-peptide (ng/mL)1.39 ± 0.651.09 ± 1.030.025Fasting insulin (mU/L)7.9 ± 5.15.7 ± 5.80.042Fasting glucose (mg/dL)88 ± 988 ± 180.830Insulin after 60min (mU/L)87.6 ± 85.853.4 ± 51.80.0361st phase insulin secretion982 ± 573745 ± 5000.012HOMA-IR1.75 ± 1.181.39 ± 2.070.303Stumvoll index (ISI)0.10 ± 0.030.09 ± 0.03 0.230
Disclosure
N.J. Tripolt: None. S. Stekovic: None. J. Url: None. F. Aberer: None. P.N. Pferschy: None. R. Riedl: None. B.M. Obermayer-Pietsch: None. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. F. Madeo: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..
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