Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16
..., p21
and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
Heat stress during the dry period affects the cow’s mammary gland development, metabolism, and immunity during the transition period. However, the effect of late-gestation heat stress on calf ...performance and immune status is unknown. Our objective was to evaluate the effect of heat stress during the final ∼45d of gestation on growth and immune function of calves. Calves (17/treatment) were born to cows that were exposed to cooling (CL) or heat stress (HT) during the dry period. Only heifer calves (CL, n=12; HT, n=9) were used in measurements of growth and immune status after birth. Heifer calves were managed under identical conditions. All were fed 3.78L of colostrum from their respective dams within 4h of birth and were weaned at 2mo of age (MOA). Body weight (BW) was obtained at weaning and then monthly until 7 MOA. Withers height (WH) was measured monthly from 3 to 7 MOA. Hematocrit and plasma total protein were assessed at birth, 1, 4, 7, 11, 14, 18, 21, 25, and 28d of age. Total serum IgG was evaluated at 1, 4, 7, 11, 14, 18, 21, 25, and 28d of age, and apparent efficiency of absorption was calculated. Peripheral blood mononuclear cells were isolated at 7, 28, 42, and 56d of age, and proliferation rate was measured by 3H-thymidine incorporation in vitro. Blood cortisol concentration was measured in the dams during the dry period and in calves in the preweaning period. Gestation length was 4d shorter for HT cows compared with CL cows. Calves from CL cows had greater BW than calves from HT cows at birth (42.5 vs. 36.5kg). Compared with CL heifers, HT heifers had decreased weaning BW (78.5 vs. 65.9kg) but similar BW (154.6 vs. 146.4kg) and WH (104.8 vs. 103.4cm) from 3 to 7 MOA. Compared with CL, heifers from HT cows had less total plasma protein (6.3 vs. 5.9g/dL), total serum IgG (1,577.3 vs. 1,057.8mg/dL), and apparent efficiency of absorption (33.6 vs. 19.2%), and tended to have decreased hematocrit (33 vs. 30%). Additionally, CL heifers had greater peripheral blood mononuclear cell proliferation relative to HT heifers (23.8 vs. 14.1 fold). Compared with CL, late-gestation HT did not affect the blood cortisol concentration of dams during the dry period or that of the calves in the preweaning period, but CL calves tended to have increased circulating cortisol at birth (7.6 vs. 5.7µg/dL). We conclude that heat stress of the dam during the dry period compromises the fetal growth and immune function of offspring from birth through weaning.
Competing interests: Since 1993 GC has worked for the World Cancer Research Fund International and the American Institute for Cancer Research (both not-for-profit organisations). Others, such as ...burgers, chips, cookies, sweets, "nuggets," energy bars, and carbonated and other sugared or sweet drinks, are more recent, at least in the quantity now manufactured. Since the 1980s, "Big Snack"--the transnational manufacturers of packaged, long shelf-life snacks designed to displace meals--have greatly increased their penetration first of high-income countries, and now of lower-income countries, including Brazil 21.
Ultraprocessed foods (UPF) are widespread in Western diets. Their consumption has been associated in recent prospective studies with increased risks of all-cause mortality and chronic diseases such ...as cancer, cardiovascular diseases, hypertension, and dyslipidemia; however, data regarding diabetes are lacking.
To assess the associations between consumption of UPF and risk of type 2 diabetes (T2D).
In this population-based prospective cohort study, 104 707 participants aged 18 years or older from the French NutriNet-Santé cohort (2009-2019) were included. Dietary intake data were collected using repeated 24-hour dietary records (5.7 per participant on average), designed to register participants' usual consumption for more than 3500 different food items. These were categorized according to their degree of processing by the NOVA classification system.
Associations between UPF consumption and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors).
A total of 104 707 participants (21 800 20.8% men and 82 907 79.2% women) were included. Mean (SD) baseline age of participants was 42.7 (14.5) years. Absolute T2D rates in the lowest and highest UPF consumers were 113 and 166 per 100 000 person-years, respectively. Consumption of UPF was associated with a higher risk of T2D (multi-adjusted hazard ratio HR for an absolute increment of 10 in the percentage of UPF in the diet, 1.15; 95% CI, 1.06-1.25; median follow-up, 6.0 years; 582 252 person-years; 821 incident cases). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet, for other metabolic comorbidities (HR, 1.13; 95% CI, 1.03-1.23), and for weight change (HR, 1.13; 95% CI, 1.01-1.27). The absolute amount of UPF consumption (grams per day) was consistently associated with T2D risk, even when adjusting for unprocessed or minimally processed food intake (HR for a 100 g/d increase, 1.05; 95% CI, 1.02-1.08).
In this large observational prospective study, a higher proportion of UPF in the diet was associated with a higher risk of T2D. Even though these results need to be confirmed in other populations and settings, they provide evidence to support efforts by public health authorities to recommend limiting UPF consumption.
ClinicalTrials.gov Identifier: NCT03335644.
AbstractObjectiveTo assess the prospective associations between consumption of ultra-processed foods and risk of cardiovascular diseases.DesignPopulation based cohort study.SettingNutriNet-Santé ...cohort, France 2009-18.Participants105 159 participants aged at least 18 years. Dietary intakes were collected using repeated 24 hour dietary records (5.7 for each participant on average), designed to register participants’ usual consumption of 3300 food items. These foods were categorised using the NOVA classification according to degree of processing.Main outcome measuresAssociations between intake of ultra-processed food and overall risk of cardiovascular, coronary heart, and cerebrovascular diseases assessed by multivariable Cox proportional hazard models adjusted for known risk factors.ResultsDuring a median follow-up of 5.2 years, intake of ultra-processed food was associated with a higher risk of overall cardiovascular disease (1409 cases; hazard ratio for an absolute increment of 10 in the percentage of ultra-processed foods in the diet 1.12 (95% confidence interval 1.05 to 1.20); P<0.001, 518 208 person years, incidence rates in high consumers of ultra-processed foods (fourth quarter) 277 per 100 000 person years, and in low consumers (first quarter) 242 per 100 000 person years), coronary heart disease risk (665 cases; hazard ratio 1.13 (1.02 to 1.24); P=0.02, 520 319 person years, incidence rates 124 and 109 per 100 000 person years, in the high and low consumers, respectively), and cerebrovascular disease risk (829 cases; hazard ratio 1.11 (1.01 to 1.21); P=0.02, 520 023 person years, incidence rates 163 and 144 per 100 000 person years, in high and low consumers, respectively). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet (saturated fatty acids, sodium and sugar intakes, dietary fibre, or a healthy dietary pattern derived by principal component analysis) and after a large range of sensitivity analyses.ConclusionsIn this large observational prospective study, higher consumption of ultra-processed foods was associated with higher risks of cardiovascular, coronary heart, and cerebrovascular diseases. These results need to be confirmed in other populations and settings, and causality remains to be established. Various factors in processing, such as nutritional composition of the final product, additives, contact materials, and neoformed contaminants might play a role in these associations, and further studies are needed to understand better the relative contributions. Meanwhile, public health authorities in several countries have recently started to promote unprocessed or minimally processed foods and to recommend limiting the consumption of ultra-processed foods.Study registrationClinicalTrials.gov NCT03335644.
Pharmacokinetics of metallic nanoparticles Lin, Zhoumeng; Monteiro-Riviere, Nancy A.; Riviere, Jim E.
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology,
March/April 2015, Letnik:
7, Številka:
2
Journal Article
Recenzirano
Metallic nanoparticles (NPs) have been widely applied in the field of nanomedicine. A comprehensive understanding of their pharmacokinetics is crucial for proper risk assessment and safe biomedical ...applications. This review focuses on gold and silver (Ag) NPs, and briefly discusses iron oxide, titanium dioxide (TiO2), and zinc oxide NPs. Pharmacokinetics of metallic NPs depends on the particle type, size, surface charge, surface coating, protein binding, exposure route, dose, and species. Generally, blood half‐life is shorter in rodents than in larger laboratory animals (e.g., rabbits or monkeys) and differs between intravenous and oral exposures. Oral, dermal, or inhalational absorption is low (≤5%), but may increase with smaller sizes, negative charge, and appropriate coatings. Metallic NPs can be distributed throughout the body, primarily accumulating in the liver, spleen, and lymph node due to nonspecific uptake by reticuloendothelial cells, and could remain in the body for ≥6 months. Metallic NPs (≤100 nm) can cross the blood–brain barrier (BBB), favored by coating with BBB‐permeable neuropeptides. Placental transfer depends on the stage of embryonic/placental maturation and surface composition, and may be enhanced by coating with biocompatible molecules (e.g., ferritin or polyethylene glycol). Renal and biliary excretion is generally low due to persistent accumulation in tissues, but renal elimination could be substantially increased with smaller sizes and specific coatings (e.g., glutathione). Physiologically based pharmacokinetic models for gold/dendrimer composite nanodevices, AgNPs, and TiO2NPs have been developed in rats and the AgNP and TiO2NP models have been extrapolated to humans to support risk assessment and nanomedicine applications. WIREs Nanomed Nanobiotechnol 2015, 7:189–217. doi: 10.1002/wnan.1304
This article is categorized under:
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Many
species are found as commensal members of the intestinal microbiota. However, imbalances of the microbiota may lead to certain infections caused by these microorganisms, mainly
,
, and
. In many ...cases, infection recurrence can occur after antibiotics, indicating the need for novel therapeutic options that act on the pathogens and also restore the microbiota. Herein, the in vitro antimicrobial activity and probiotic potential of clinical and reference strains of
and
were investigated against
species. Antimicrobial activity was evaluated by the agar spot test and inhibition of gas production. Then, the probiotic potential of selected strains was assessed by analyzing their coaggregation ability, adhesive properties to host cells and mucin, tolerance to acidic pH and bile salts, and antimicrobial susceptibility profiles.
ATCC 8014 was the most promising strain based on its inhibitory activity against
spp. Also, this strain met criteria to be considered a probiotic based on its coaggregation ability, adhesive properties, and tolerance to harsh pH and bile acid salt conditions. The results indicate that among the studied strains,
ATCC 8014 presents probiotic potential for controlling infections induced by the studied
species and should be further evaluated in in vivo animal models.
Calves born to cows exposed to heat stress during late gestation (i.e., the dry period) have lower birth weight and weaning weight and compromised passive immune transfer compared with those born to ...dams that are cooled. However, it is unknown if heat stress in utero has carryover effects after weaning. The objective was to evaluate the effect of heat stress (HT) or cooling (CL) in late gestation dairy cows on the survival, growth, fertility, and milk production in the first lactation of their calves. Data of animals obtained from previous experiments conducted during 5 consecutive summers in Florida were pooled and analyzed. Cows were dried off 46d before expected calving and randomly assigned to 1 of 2 treatments, HT or CL. Cooled cows were housed with sprinklers, fans, and shade, whereas only shade was provided to HT cows. Within 4h of birth, 3.8 L of colostrum was fed to calves from both groups of cows. All calves were managed in the same manner and weaned at 49d of age. Birth weight and survival of 146 calves (HT=74; CL=72) were analyzed. Additionally, body weight, growth rate, fertility, and milk production in the first lactation from 72 heifers (HT=34; CL=38) were analyzed. As expected, HT calves were lighter (means ± SEM; 39.1±0.7 vs. 44.8±0.7kg) at birth than CL calves. Cooled heifers were heavier up to 1yr of age, but had similar total weight gain (means ± SEM; 305.8±6.3 vs. 299.1±6.3kg, respectively) compared with HT heifers. No effect of treatment was observed on age at first insemination (AI) and age at first parturition. Compared with CL heifers, HT heifers had a greater number of services per pregnancy confirmed at d 30 after AI, but no treatment effect was observed on number of services per pregnancy confirmed at d 50 after AI. A greater percentage of CL heifers reached first lactation compared with HT heifers (85.4 vs. 65.9%). Moreover, HT heifers produced less milk up to 35wk of the first lactation compared with CL heifers (means ± SEM; 26.8±1.7 vs. 31.9±1.7kg/d), and no difference in body weight during lactation was observed (means ± SEM; HT: 568.4±14.3kg; CL: 566.5±14.3kg). These data suggest that heat stress during the last 6wk of gestation induces a phenotype that negatively affects survival and milk production up to and through the first lactation of offspring.
Lactating cows that experience heat stress will have reduced dry matter intake and milk yield and shift metabolism, which ultimately reduces the efficiency of milk production. Dry cows that are heat ...stressed similarly experience lower intake, reduced mammary growth, and compromised immune function that ultimately results in a poorer transition into lactation and lower milk yield in the next lactation. A recent focus in our laboratory is on the effects of late gestation, in utero heat stress on calf survival and performance. We have completed a series of studies to examine preweaning growth and health, and later reproductive and productive responses, in an attempt to quantify acute and persistent effects of in utero heat strain. Late gestation heat stress results in calves with lower body weight at birth, shorter stature at weaning, and failure to achieve the same weight or height at 12 mo of age observed in calves from dams that are cooled when dry. A portion of the reduced growth may result from the lower immune status observed in calves heat stressed in utero, which begins with poorer apparent efficiency of immunoglobulin absorption and extends to lower survival rates through puberty. Heat-stressed calves, however, have permanent shifts in metabolism that are consistent with greater peripheral accumulation of energy and less lean growth relative to those from cooled dams. Comparing reproductive performance in calves heat stressed versus those cooled in utero, we observe that the cooled heifers require fewer services to attain pregnancy and become pregnant at an earlier age. Tracking the milk production in calves that were heat stressed in utero versus those cooled in late gestation revealed a significant reduction of yield in the first lactation, approximately 5 kg/d through 35 wk of lactation, despite similar body weight and condition score at calving. These observations indicate that a relatively brief period of heat stress in late gestation dramatically alters the health, growth, and ultimate performance of dairy calves. Thus, it is critical to effectively manage heat stress of dry cows to avoid negative effects on the calf.
Prevention of chronic diseases has therefore been considered a public health challenge in the past decades 2. Besides physical activity, the nutritional quality of the diet is a major modifiable risk ...factor for weight management, with strong levels of evidence for protective factors (i.e., dietary fibre, Mediterranean diets) and risk factors (i.e., high energy density, free sugars, sugar sweetened drinks, and Western-type diets) 5,7. Another characteristic of UPFs is that they are obtained after sequences of several processes, such as high-temperature extrusion, moulding, and pre-frying, and include several food additives and industrial ingredients used to imitate or enhance sensory qualities of foods or to disguise unpalatable aspects of the final product; they are also often in contact with synthetic packaging materials for long periods 25. Consistently, several cross-sectional and ecological studies have substantiated a positive association between UPF consumption and obesity 23,35–39, but prospective studies are lacking, as only 2 of them—one in Spain 40 and one in Brazil 41—were conducted; both relied on dietary data from food frequency questionnaires (FFQs) and studied the contribution of UPF to energy intake and therefore did not account for low-calorie and artificially sweetened products. Several indicators of the nutritional quality of the diet were also computed based on average dietary intakes from baseline 24-hour dietary records and were used as covariates: daily nutrient intake (sugar, fibre, sodium, and saturated fatty acid SFA) calculated using the food composition database; consumptions of several food groups (fruit, vegetables, and sugary drinks); and healthy and Western dietary patterns, derived from Principal Component Analysis (see Method D in S1 Appendix).
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