Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment ...remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Summary
Sugar‐sweetened beverages (SSBs) are the single largest source of added sugar and the top source of energy intake in the U.S. diet. In this review, we evaluate whether there is sufficient ...scientific evidence that decreasing SSB consumption will reduce the prevalence of obesity and its related diseases. Because prospective cohort studies address dietary determinants of long‐term weight gain and chronic diseases, whereas randomized clinical trials (RCTs) typically evaluate short‐term effects of specific interventions on weight change, both types of evidence are critical in evaluating causality. Findings from well‐powered prospective cohorts have consistently shown a significant association, established temporality and demonstrated a direct dose–response relationship between SSB consumption and long‐term weight gain and risk of type 2 diabetes (T2D). A recently published meta‐analysis of RCTs commissioned by the World Health Organization found that decreased intake of added sugars significantly reduced body weight (0.80 kg, 95% confidence interval CI 0.39–1.21; P < 0.001), whereas increased sugar intake led to a comparable weight increase (0.75 kg, 0.30–1.19; P = 0.001). A parallel meta‐analysis of cohort studies also found that higher intake of SSBs among children was associated with 55% (95% CI 32–82%) higher risk of being overweight or obese compared with those with lower intake. Another meta‐analysis of eight prospective cohort studies found that one to two servings per day of SSB intake was associated with a 26% (95% CI 12–41%) greater risk of developing T2D compared with occasional intake (less than one serving per month). Recently, two large RCTs with a high degree of compliance provided convincing data that reducing consumption of SSBs significantly decreases weight gain and adiposity in children and adolescents. Taken together, the evidence that decreasing SSBs will decrease the risk of obesity and related diseases such as T2D is compelling. Several additional issues warrant further discussion. First, prevention of long‐term weight gain through dietary changes such as limiting consumption of SSBs is more important than short‐term weight loss in reducing the prevalence of obesity in the population. This is due to the fact that once an individual becomes obese, it is difficult to lose weight and keep it off. Second, we should consider the totality of evidence rather than selective pieces of evidence (e.g. from short‐term RCTs only). Finally, while recognizing that the evidence of harm on health against SSBs is strong, we should avoid the trap of waiting for absolute proof before allowing public health action to be taken.
A wide variety of industrial applications require materials with high strength and ductility. Unfortunately, the strategies for increasing material strength, such as processing to create line defects ...(dislocations), tend to decrease ductility. We developed a strategy to circumvent this in inexpensive, medium manganese steel. Cold rolling followed by low-temperature tempering developed steel with metastable austenite grains embedded in a highly dislocated martensite matrix. This deformed and partitioned (D and P) process produced dislocation hardening but retained high ductility, both through the glide of intensive mobile dislocations and by allowing us to control martensitic transformation. The D and P strategy should apply to any other alloy with deformation-induced martensitic transformation and provides a pathway for the development of high-strength, high-ductility materials.
Bringing together the key ideas from nonequilibrium statistical mechanics and powerful methodology from quantum field theory, this book captures the essence of nonequilibrium quantum field theory. ...Beginning with the foundational aspects of the theory, the book presents important concepts and useful techniques, discusses issues of basic interest, and shows how thermal field, linear response, kinetic theories and hydrodynamics emerge. It also illustrates how these concepts and methodology are applied to current research topics including nonequilibrium phase transitions, thermalization in relativistic heavy ion collisions, the nonequilibrium dynamics of Bose-Einstein condensation, and the generation of structures from quantum fluctuations in the early Universe. Divided into five parts, with each part addressing a particular stage in the conceptual and technical development of the subject, this self-contained book is a valuable reference for graduate students and researchers in particle physics, gravitation, cosmology, atomic-optical and condensed matter physics.
Diabetes and cancer have been closely linked to each other epidemiologically and biologically. Convincing evidence indicates that diabetes (mainly type 2) is associated with increased risk for ...several cancers (colorectal, breast, endometrium, liver, pancreas, and bladder).
Plant-based diets have been recommended to reduce the risk of type 2 diabetes (T2D). However, not all plant foods are necessarily beneficial. We examined the association of an overall plant-based ...diet and hypothesized healthful and unhealthful versions of a plant-based diet with T2D incidence in three prospective cohort studies in the US.
We included 69,949 women from the Nurses' Health Study (1984-2012), 90,239 women from the Nurses' Health Study 2 (1991-2011), and 40,539 men from the Health Professionals Follow-Up Study (1986-2010), free of chronic diseases at baseline. Dietary data were collected every 2-4 y using a semi-quantitative food frequency questionnaire. Using these data, we created an overall plant-based diet index (PDI), where plant foods received positive scores, while animal foods (animal fats, dairy, eggs, fish/seafood, poultry/red meat, miscellaneous animal-based foods) received reverse scores. We also created a healthful plant-based diet index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, sweets/desserts) and animal foods received reverse scores. Lastly, we created an unhealthful plant-based diet index (uPDI) by assigning positive scores to less healthy plant foods and reverse scores to healthy plant foods and animal foods. We documented 16,162 incident T2D cases during 4,102,369 person-years of follow-up. In pooled multivariable-adjusted analysis, both PDI and hPDI were inversely associated with T2D (PDI: hazard ratio HR for extreme deciles 0.51, 95% CI 0.47-0.55, p trend < 0.001; hPDI: HR for extreme deciles 0.55, 95% CI 0.51-0.59, p trend < 0.001). The association of T2D with PDI was considerably attenuated when we additionally adjusted for body mass index (BMI) categories (HR 0.80, 95% CI 0.74-0.87, p trend < 0.001), while that with hPDI remained largely unchanged (HR 0.66, 95% CI 0.61-0.72, p trend < 0.001). uPDI was positively associated with T2D even after BMI adjustment (HR for extreme deciles 1.16, 95% CI 1.08-1.25, p trend < 0.001). Limitations of the study include self-reported diet assessment, with the possibility of measurement error, and the potential for residual or unmeasured confounding given the observational nature of the study design.
Our study suggests that plant-based diets, especially when rich in high-quality plant foods, are associated with substantially lower risk of developing T2D. This supports current recommendations to shift to diets rich in healthy plant foods, with lower intake of less healthy plant and animal foods.
Background Whether marine omega-3 supplementation is associated with reduction in risk of cardiovascular disease (CVD) remains controversial. Methods and Results This meta-analysis included ...study-level data from 13 trials. The outcomes of interest included myocardial infarction, coronary heart disease (CHD) death, total CHD, total stroke, CVD death, total CVD, and major vascular events. The unadjusted rate ratios were calculated using a fixed-effect meta-analysis. A meta-regression was conducted to estimate the dose-response relationship between marine omega-3 dosage and risk of each prespecified outcome. During a mean treatment duration of 5.0 years, 3838 myocardial infarctions, 3008 CHD deaths, 8435 total CHD events, 2683 strokes, 5017 CVD deaths, 15 759 total CVD events, and 16 478 major vascular events were documented. In the analysis excluding REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), marine omega-3 supplementation was associated with significantly lower risk of myocardial infarction (rate ratio RR 95% CI: 0.92 0.86, 0.99;
=0.020), CHD death (RR 95% CI: 0.92 0.86, 0.98;
=0.014), total CHD (RR 95% CI: 0.95 0.91, 0.99;
=0.008), CVD death (RR 95% CI: 0.93 0.88, 0.99;
=0.013), and total CVD (RR 95% CI: 0.97 0.94, 0.99;
=0.015). Inverse associations for all outcomes were strengthened after including REDUCE-IT while introducing statistically significant heterogeneity. Statistically significant linear dose-response relationships were found for total CVD and major vascular events in the analyses with and without including REDUCE-IT. Conclusions Marine omega-3 supplementation lowers risk for myocardial infarction, CHD death, total CHD, CVD death, and total CVD, even after exclusion of REDUCE-IT. Risk reductions appeared to be linearly related to marine omega-3 dose.
Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains ...unclear. Therefore, we aimed to evaluate this association in two cohorts of US women.
We followed 69,269 women aged 42-67 in Nurses' Health Study I (NHS I, 1988-2008), and 107,915 women aged 25-42 in NHS II (1989-2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2-4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18-20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1-2, 3-9, 10-19, and ≥20 years of shift work were 1.05 (1.00-1.11), 1.20 (1.14-1.26), 1.40 (1.30-1.51), and 1.58 (1.43-1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98-1.08), 1.06 (1.01-1.11), 1.10 (1.02-1.18), and 1.24 (1.13-1.37, p-value for trend <0.001).
Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes.
Sugar-sweetened beverages (SSBs) have little nutritional value and a robust body of evidence has linked the intake of SSBs to weight gain and risk of type 2 diabetes (T2D), cardiovascular disease ...(CVD), and some cancers. Metabolic Syndrome (MetSyn) is a clustering of risk factors that precedes the development of T2D and CVD; however, evidence linking SSBs to MetSyn is not clear. To make informed recommendations about SSBs, new evidence needs to be considered against existing literature. This review provides an update on the evidence linking SSBs and cardiometabolic outcomes including MetSyn. Findings from prospective cohort studies support a strong positive association between SSBs and weight gain and risk of T2D and coronary heart disease (CHD), independent of adiposity. Associations with MetSyn are less consistent, and there appears to be a sex difference with stroke with greater risk in women. Findings from short-term trials on metabolic risk factors provide mechanistic support for associations with T2D and CHD. Conclusive evidence from cohort studies and trials on risk factors support an etiologic role of SSB in relation to weight gain and risk of T2D and CHD. Continued efforts to reduce intake of SSB should be encouraged to improve the cardiometabolic health of individuals and populations.
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