Codelivery of anti-CD47 antibody and chlorin e6 using a dual pH-sensitive nanodrug for photodynamic immunotherapy of osteosarcoma

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis.Immunotherapy has shown great potential in the treatment of osteosarcoma.However,the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment.The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment.Here,we prepared a dual pH-sensitive nanocarrier,loaded with the photosensitizer Chlorin e6(Ce6)and CD47 monoclonal antibodies(aCD47),to deliver synergistic photodynamic and immunotherapy of osteosarcoma.On laser irradiation,Ce6 can generate reactive oxygen species(ROS)to kill cancer cells directly and induces immunogenic tumor cell death(ICD),which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47.Moreover,both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages,promote antigen presentation,and eventually induce T lymphocyte-mediated antitumor immunity.Overall,the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma,which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.

Overweight, obesity, and screen-time viewing among Chinese school-aged children: National prevalence estimates from the 2016 Physical Activity and Fitness in China—The Youth Study

Purpose: This study presents the most recent estimates of prevalence of overweight, obesity, and screen-time viewing among Chinese school-aged children. Demographic differences in these estimates between sexes and resident locales were also examined.Methods: Cross-sectional analyses of 116,615 Chinese school children 9 to 17 years of age who participated in the 2016 Physical Activity and Fitness in China—The Youth Study project. Outcomes were the prevalence of children's overweight(85 th ≤ body mass index(BMI) < 95 th percentile) and obesity(BMI ≥95 th percentile)(defined by the Working Group on Obesity in China) and not meeting screen-time viewing recommendations("not meeting" was defined as more than 2 h per day of viewing activities after school). Analyses were conducted on the whole sample and by school grade cohorts(primary, junior middle, and junior high schools), sex, and residence locales(urban, rural).Results: Overall, 14.4%(95% confidence interval(CI): 13.8%–15.0%) of children and adolescents were overweight, 11.9%(95%CI: 11.0%–13.0%) were obese, and 36.8%(95%CI: 34.7%–38.9%) did not meet screen-time viewing recommendations. Across the 3-grade cohorts, boys were more likely to be obese than girls, and primary and junior middle school children living in urban areas were more likely to be obese than those living in rural areas. Primary and junior middle school boys were less likely to meet screen-time recommendations than girls, and junior high school children living in urban areas were less likely to meet screen-time recommendations than school children of the same grades living in rural areas.Conclusion: In 2016, the prevalence of obesity among Chinese school children was about 12%, and about 37% of them did not meet screen-time viewing recommendations. The prevalence of obesity and sedentary behavior was generally higher among boys than among girls, and it was higher for children living in urban areas than for those living in rural areas.

Meeting 24-h movement guidelines: Prevalence, correlates, and the relationships with overweight and obesity among Chinese children and adolescents

Background:Meeting 24-h movement guidelines by children and adolescents has been associated with improved indicators of health,although it has been under-studied in China.Hence,this study aimed to investigate the prevalence of meeting the 24-h movement guidelines,its correlates,and its relationships with body mass index in children and adolescents in China.Methods:Cross-sectional data from the 2017 Youth Study in China of 114,072 children and adolescents(mean age=13.75 years,49.18%boys)were used.Meeting 24-h movement guidelines(60 min of daily moderate-to-vigorous physical activity,2 h of daily leisure screen time,911 h and 810 h nightly sleep duration for 613-year-olds and 1417-year-olds,respectively)and height and weight of all participants were assessed.The prevalence of meeting the 24-h movement guidelines and World Health Organization weight status categories were determined.Generalized linear models were used to determine the correlates of meeting the 24-h movement guidelines and the relationships of meeting the 24-h movement guidelines with overweight(OW)and obesity(OB).Results:Only 5.12%of Chinese children and adolescents met the 24-h movement guidelines,and 22.44%were classified as OW/OB.Older children and adolescents were less likely to meet the 24-h movement guidelines.Parental education level and family income were positively related to meeting the 24-h movement guidelines.Children and adolescents meeting the 24-h movement guidelines showed lower odds ratios for OW/OB.Compared with participants meeting the 24-h movement guidelines,boys in 4th6th grades met none of the recommendations(OR=1.22,95%CI:1.061.40),met the screen time recommendation only(OR=1.13,95%CI:1.011.28),met the nightly sleep duration recommendation only(OR=1.14,95%CI:1.031.28),and had significantly higher odds ratios for OW/OB.Similar trends were observed for girls in 4th6th grades:meeting none of the guidelines(OR=1.35,95%CI:1.141.59),meeting sleep duration guidelines only(OR=1.23,95%CI:1.081.39),and meeting moderate-to-vigorous physical activity+nightly sleep duration guidelines(OR=1.24,95%CI:1.011.54).For girls in 7th9th grades,the following trend was observed:meeting none of the guidelines(OR=1.30,95%CI:1.011.67).Conclusion:Very few Chinese children and adolescents met the 24-h movement guidelines.Age(negatively correlated),parental education level,and family income(both positively correlated)were correlates of meeting the 24-h movement guidelines.Children and adolescents meeting the 24-h movement guidelines were more likely to have lower risks for OW/OB,especially in the youngest age group(Grades 46);and girls in the middle age group(Grades 79)were also more likely to have lower risks for OW/OB.Further research studies should explore additional correlates and determinants for meeting the 24-h movement guidelines.Also,future studies should use longitudinal or interventional designs to determine the relationships between meeting the 24-h movement guidelines and OW/OB and other health indicators,while taking sex and age differences into account.

Prevalence and correlates of meeting the muscle-strengthening exercise recommendations among Chinese children and adolescents:Results from 2019 Physical Activity and Fitness in China—The Youth Study

Purpose This study aimed to describe the national prevalence of Chinese children and adolescents who met the World Health Organization muscle-strengthening exercise(MSE)recommendations and identify correlates of meeting the MSE recommendations.Methods Cross-sectional data from the 2019 Physical Activity and Fitness in China—The Youth Study,a nationally representative sample of Chinese children and adolescents(n=80,413;mean age=13.7 years;53.9%girls)and their parents,were analyzed.Children and adolescents who reported engaging≥3 days(up to 7 days)of MSE per week were classified as meeting the MSE recommendations.MSE,demographics,lifestyle behaviors(sport participation,moderate-to-vigorous physical activity,screen time,and sleep duration),exercise intention,peer and parental support,and parental MSE participation were assessed through self-reports.Logistic regression models were used to determine the correlates of meeting the MSE recommendations.The analyses were completed in 2020.Results Overall,39.3%of children and adolescents met the MSE recommendations.Girls,10th-12th graders,minorities,those from lower income households and those from families with lower parental education were less likely to meet the MSE recommendations.Children and adolescents who were proficient in≥2 sports were more likely to meet the MSE recommendations(adjusted odds ratio(aOR)=1.44,95%confidence interval(95%CI):1.26-1.65),as were those with more moderate-to-vigorous physical activity(aOR=1.57,95%CI:1.53-1.61).Additionally,children and adolescents with high exercise intention(aOR=1.60,95%CI:1.51-1.69),those whose parents met the adult MSE recommendations(aOR=1.46,95%CI:1.40-1.52),and those who received high peer(aOR=1.27,95%CI:1.20-1.34)and parental support(aOR=1.07,95%CI:1.04-1.12)were more likely to meet the MSE recommendations.Conclusion Less than two-fifths of Chinese children and adolescents met the World Health Organization MSE recommendations.The correlates identified in our study can help inform the development of school and community based strategies and policies to enhance participation in MSE and improve muscular fitness of all Chinese children and adolescents.

High speed laser cladding as a new approach to prepare ultra-high temperature ceramic coatings

Ultra-high temperature ceramic(UHTC)coatings are used to protect the hot-end components of hypervelocity aerocrafts from thermal ablation.This study provides a new approach to fabricate UHTC coatings with high speed laser cladding(HSLC)technology,and places more emphasis on investigating the formation mechanism,phase compositions,and mechanical properties of HSLC-UHTC coatings.Results show that a well-bonded interface between the coating and the tantalum alloy substrate can be formed.The coating is mainly composed of(Zr,Ta)C ceramic solid solution phase with a content of higher than 90% by volume and Ta(W)metal solid solution phase.At a relatively high powder feeding rate,the ZrC ceramic phase appears in the coating while a dense ZrC UHTC top layer with a thickness of up to~50μm is successfully fabricated.As for the mechanical properties of the HSLC coatings,the fracture toughness of the coating decreases with the increase of powder feeding rate.The increase of carbide solid solution phase can significantly improve the high temperature microhardness(552.7±1.8 HV0.5@1000℃).The innovative design of HSLC ZrC-based coatings on refractory alloys accomplishes continuous transitions on microstructure and properties from the substrate to the UHTC top layer,which is a very promising candidate scheme for thermal protection coating.

Twins-like nanodrugs synchronously transport in blood and coalesce inside tumors for sensitive ultrasound imaging and triggerable penetrative drug delivery

Nanodrugs capable of aggregating in the tumor microenvironment(TME)have demonstrated great efficiency in improving the therapeutic outcome.Among vari-ous approaches,the strategy utilizing electrostatic interaction as a driving force to achieve intratumor aggregation of nanodrugs has attracted great attention.However,the great difference between the two nanodrugs with varied physicochemical prop-erties makes their synchronous transport in blood circulation and equal-opportunity tumor uptake impossible,which significantly detracts from the beneficial effects of nanodrug aggregation inside tumors.We herein propose a new strategy to construct a pair of extremely similar nanodrugs,referred to as“twins-like nanodrugs(TLNs)”,which have identical physicochemical properties including the same morphology,size,and electroneutrality to render them the same blood circulation time and tumor entrance.The 1:1 mixture of TLNs(TLNs-Mix)intravenously injected into a mouse model efficiently accumulates in tumor sites and then transfers to oppositely charged nanodrugs for electrostatic interaction-driven coalescence via responding to matrix metalloproteinase-2(MMP-2)enriched in tumor.In addition to enhanced tumor retention,the thus-formed micron-sized aggregates show high echo intensity essen-tial for ultrasound imaging as well as ultrasound-triggered penetrative drug delivery.Owing to their distinctive features,the TLNs-Mix carrying sonosensitizer,immune adjuvant,and ultrasound contrast agent exert potent sonodynamic immunotherapy against hypovascular hepatoma,demonstrating their great potential in treating solid malignancies.

Theranostic nanosystem mediating cascade catalytic reactions for effective immunotherapy of highly immunosuppressive and poorly penetrable pancreatic tumor

The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine has recently shown attractive potential in cancer immunotherapy, it remains a great challenge to achieve efficient drug delivery and potent immune activation.Here, a stimuli-responsive nanosystem, comprising superparamagnetic iron oxide nanocrystals and nitric oxide(NO) donors,was developed for in-situ triggered catalytic cascade reaction to produce abundant free radicals and remodel the anti-tumor immunity. The nanosystem was activated in the tumor microenvironment to produce NO which dilated the tumor vasculature for efficient drug delivery, and the iron oxide nanocrystals catalyzed the reaction of NO to generate reactive oxygen-nitrogen species(RONS) with high cytotoxicity. Moreover, owing to the catalytic cascade reactions mediated by the nanosystem, the tumor associated macrophages(TAMs) were converted to a proinflammatory M1 phenotype and tumor infiltration of effector T cells was promoted to result in potent anti-tumor immunotherapy which could be readily monitored with magnetic resonance imaging(MRI).