Magnetic hyperthermia therapy (MHT) is noninvasive and features excellent tissue penetration for deep-seated tumors, but unfortunately, it suffers the low therapeutic efficacy due to the limited ...magneto-thermal efficiency and insufficient intratumor accumulation of conventional intravenous-injected magnetic nanoparticles, which are actually mostly sequestered by the mononuclear phagocyte system, especially the liver. Such a disadvantageous characteristic of preferential liver uptake is here exploited, for the first time as far as we know, to treat orthotopic liver cancer by mild MHT using specially designed composite magnetic nanoparticles. A kind of core–shell-structured and Zn2+-doped Zn-CoFe2O4@Zn-MnFe2O4 superparamagnetic nanoparticles (ZCMF) has been synthesized which exhibits excellent and highly controllable magnetic hyperthermia performance owing to an exchange-coupled magnetism between the core and shell, and Zn2+ doping. The controllable mild MHT at 43–44 °C based on ZCMF demonstrates almost complete inhibition of liver cancer cell proliferation and tumor growth, which is associated with the suppression of heat shock protein 70 (HSP70) expression. More importantly, the mild MHT-treated liver cancer cells are capable of activating natural killer (NK) cells by dramatically upregulating the expression of UL16-binding proteins (ULBPs), ligands of natural killer group 2 member D (NKG2D). As a result, the growth of both xenograft tumors and orthotopic liver tumors were almost completely suppressed under mild MHT via induced NK-cell-related antitumor immunity in vivo. This work not only evidences the great potential of mild MHT but also reveals the underlying immunity activation mechanism in liver cancer treatment by mild MHT.
Metabolic reprogramming is an emerging hallmark of cancer cells, in which cancer cells exhibit distinct metabolic phenotypes to fuel their proliferation and progression. The significant advancements ...made in the area of metabolic reprogramming make possible new strategies for overcoming malignant cancer, including triple-negative breast cancer. Triple-negative breast cancer (TNBC) is associated with high histologic grade, aggressive phenotype, and poor prognosis. Even though triple-negative breast cancer patients benefit from standard chemotherapy, they still face high recurrence rates and are more likely to develop resistance to chemotherapeutic drugs. Therefore, there is an urgent need to explore vulnerabilities of triple-negative breast cancer and develop novel therapeutic drugs to improve clinical outcomes for triple-negative breast cancer patients. Metabolic reprogramming may provide promising therapeutic targets for the treatment of triple-negative breast cancer. In this paper, we primarily discuss how triple-negative breast cancer cells reprogram their metabolic phenotype and that of stromal cells in the microenvironment to survive under nutrient-poor conditions. Considering that metastasis and chemoresistance are the main contributors to mortality in triple-negative breast cancer patients, we also focus on the role of metabolic adaption in mediating metastasis and chemoresistance of triple-negative breast cancer tumors.
Quarantine and isolation measures urgently adopted to control the COVID-19 pandemic might potentially have negative psychological and social effects. We conducted this cross-sectional, nationwide ...study to ascertain the psychological effect of quarantine and identify factors associated with mental health outcomes among population quarantined to further inform interventions of mitigating mental health risk especially for vulnerable groups under pandemic conditions. Sociodemographic data, attitudes toward the COVID-19, and mental health measurements of 56,679 participants from 34 provinces in China were collected by an online survey from February 28 to March 11, 2020. Of the 56,679 participants included in the study (mean SD age, 36.0 8.2 years), 27,149 (47.9%) were male and 16,454 (29.0%) ever experienced home confinement or centralized quarantine during COVID-19 outbreak. Compared those without quarantine and adjusted for potential confounders, quarantine measures were associated with increased risk of total psychological outcomes (prevalence, 34.1% vs 27.3%; odds ratio OR, 1.34; 95% CI, 1.28-1.39; P < 0.001). Multivariable logistic regression analyses showed that vulnerable groups of the quarantined population included those with pre-existing mental disorders or chronic physical diseases, frontline workers, those in the most severely affected areas during outbreak, infected or suspected patients, and those who are less financially well-off. Complying with quarantine, being able to take part in usual work, and having adequate understanding of information related to the outbreak were associated with less mental health issues. These results suggest that quarantine measures during COVID-19 pandemic are associated with increased risk of experiencing mental health burden, especially for vulnerable groups. Further study is needed to establish interventions to reduce mental health consequences of quarantine and empower wellbeing especially in vulnerable groups under pandemic conditions.
Alzheimer's disease (AD), the most common form of dementia, is highly prevalent in older adults. The main clinical feature is the progressive decline of memory function, which eventually leads to the ...decline of cognitive function. At present, the pathogenesis of AD is unclear. In the disease process, synaptic changes are the key. Recent studies have shown that the dysregulation of RNA methylation is related to many biological processes, including neurodevelopment and neurodegenerative diseases. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNA. In this study, RNA m6A methylation was quantified in APP/PS1 transgenic mice, which is an AD mouse model, and C57BL/6 control mice, and data showed that m6A methylation was elevated in the cortex and the hippocampus of APP/PS1 transgenic mice. Next, the alterations of m6A RNA methylation in AD and in C57BL/6 mice were investigated using high-throughput sequencing. Genome-wide maps of m6A mRNA showed that the degrees of m6A methylation were higher in many genes and lower in others in AD mice. Interestingly, the expression of the m6A methyltransferase METTL3 was elevated and that of the m6A demethylase FTO was decreased in AD mice. The data were analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and pathways that might be related to synaptic or neuron development and growth were constructed. The related pathways and genes predicted the potential roles of the differentially expressed m6A methylation RNA in AD. Collectively, our findings demonstrate that the m6A methylation of RNA promotes the development of AD.
Cancer immunotherapy shows promising potential in future cancer treatment but unfortunately is clinically unsatisfactory due to the low therapeutic efficacy and the possible severe immunotoxicity. ...Here we show a combined magnetic hyperthermia therapy (MHT) and checkpoint blockade immunotherapy for both primary tumor ablation and mimetic metastatic tumor inhibition. Monodispersed, high-performance superparamagnetic CoFe2O4@MnFe2O4 nanoparticles were synthesized and used for effective MHT-induced thermal ablation of primary tumors. Simultaneously, numerous tumor-associated antigens were produced to promote the maturation and activation of dendritic cells (DCs) and cytotoxic T cells for effective immunotherapy of distant mimetic metastatic tumors in a tumor-bearing mice model. The combined MHT and checkpoint blockade immunotherapy demonstrate the great potentials in the fight against both primary and metastatic tumors.
Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of ...hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC HR
: 0.48 (95% CI: 0.33-0.69) and 0.48 (95% CI: 0.28-0.81), respectively and CLD mortality HR
: 0.21 (95% CI: 0.13-0.33) and 0.15 (95% CI: 0.08-0.30), respectively, whereas plasma levels of saturated fatty acids are positively associated with these outcomes HR
: 3.55 (95% CI: 2.25-5.61) for HCC and 6.34 (95% CI: 3.68-10.92) for CLD mortality. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.
Objective
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder. Recent studies report that long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of various diseases. ...This study explored the molecular mechanism of lncRNA growth arrest specific 5 (GAS5) in regulating the T helper 17 (Th17)/regulatory T (Treg) cell balance in MG.
Methods
GAS5 and miR-23a expression levels were detected by quantitative reverse transcription polymerase chain reaction. Flow cytometry was performed to examine the proportion of Th17 and Treg cells in CD4+ T cells from MG patients. The interaction between GAS5 and miR-23a was verified by luciferase reporter and RNA immunoprecipitation assays. Levels of Th17 and Treg-related proteins were examined using western blots and enzyme-linked immunosorbent assays.
Results
GAS5 expression levels were significantly decreased in the CD4+ T cells of MG patients, and GAS5 overexpression restrained Th17 differentiation in CD4+ T cells. Moreover, miR-23a was confirmed as a downstream target of GAS5 and negatively regulated by GAS5 through a direct interaction. Further exploration showed that GAS5 can inhibit Th17 differentiation by downregulating miR-23a.
Conclusion
Collectively, our results indicate that GAS5 can regulate the Th17/Treg balance by targeting miR-23a expression, providing a scientific basis for clinical therapeutic development for MG.
Animal husbandry is a vital sector in China's agriculture sector, contributing to over one-third of its agricultural output, and more than 40% of farmers' income. However, this industry is vulnerable ...to risks arising from production and operation, such as disease outbreaks, natural disasters, and market fluctuations. Livestock insurance can help mitigate these risks, but the lack of reliable data on shed environments has hindered its effectiveness. The objective of this study is to propose a livestock shed environmental regulatory platform that utilizes blockchain and the Internet of Things to ensure data authenticity, real-time monitoring, and transparency in the regulatory process. The platform also automates the insurance process, reducing costs and improving efficiency. The proposed platform employs blockchain to ensure data authenticity and devices to monitor and collect real-time environmental data. It also utilizes smart contracts to automate the insurance process, from negotiating and signing contracts to making insurance claims. The system's design rationale, architecture, and implementation are detailed. The proposed platform has been implemented and currently manages over 300,000 livestock animals with more than 350,000 insurance contracts signed. The use of blockchain and the Internet of Things has ensured data authenticity, real-time monitoring, and transparency in the regulatory process, while the automation of the insurance process has reduced costs and improved efficiency. The proposed livestock shed environmental regulatory platform has the potential to improve the effectiveness of livestock insurance in China by addressing the critical issue of data reliability. The use of blockchain and the Internet of Things has enabled real-time monitoring, data authenticity, and transparency in the regulatory process, while the automation of the insurance process has improved efficiency and reduced costs. This platform could serve as a model for other countries looking to improve the effectiveness of their livestock insurance programs.
Sleep disturbances are highly prevalent in pregnancy and are frequently overlooked as a potential cause of significant morbidity. The association between sleep disturbances and pregnancy outcomes ...remains largely controversial and needs to be clarified to guide management. To evaluate the association between sleep disturbances and maternal complications and adverse fetal outcomes, we performed a systematic search of PubMed, Embase and Web of Science for English-language articles published from inception to March 6, 2020, including observational studies of pregnant women with and without sleep disturbances assessing the risk of obstetric complications in the antenatal, intrapartum or postnatal period, and neonatal complications. Data extraction was completed independently by two reviewers. We utilized the Newcastle–Ottawa Scales to assess the methodological quality of included studies and random-effect models to pool the associations. A total of 120 studies with 58,123,250 pregnant women were included. Sleep disturbances were assessed, including poor sleep quality, extreme sleep duration, insomnia symptoms, restless legs syndrome, subjective sleep-disordered breathing and diagnosed obstructive sleep apnea. Significant associations were found between sleep disturbances in pregnancy and a variety of maternal complications and adverse fetal outcomes. Overall sleep disturbances were significantly associated with pre-eclampsia (odds ratio = 2.80, 95% confidence interval: 2.38–3.30), gestational hypertension (1.74, 1.54–1.97), gestational diabetes mellitus (1.59, 1.45–1.76), cesarean section (1.47, 1.31–1.64), preterm birth (1.38, 1.26–1.51), large for gestational age (1.40, 1.11–1.77), and stillbirth (1.25, 1.08–1.45), but not small for gestational age (1.03, 0.92–1.16), or low birth weight (1.27, 0.98–1.64). Sleep disturbances were related to higher morbidities in pregnant women who are 30 y or older and overweight before pregnancy. The findings indicate that sleep disturbances, which are easily ignored and treatable for both pregnant women and clinical services, deserve more attention from health care providers during prenatal counseling and health care services.
Elevated homocysteine (Hcy) levels have been linked to the development of cardiovascular diseases, notably endothelial dysfunction, a critical precursor to atherosclerosis. In this extensive ...investigation, we explore the intricate pathways through which Hcy influences endothelial dysfunction, with particular attention to the CXCL10/CXCR3 axis. Employing a dual approach encompassing both in vitro and in vivo models, we scrutinize the repercussions of Hcy exposure on endothelial functionality. Our results reveal that Hcy significantly impairs crucial endothelial processes, including cell migration, proliferation, and tube formation. Concomitantly, Hcy upregulates the expression of adhesion molecules, exacerbating endothelial dysfunction. In a murine hyperhomocysteinemia (HHcy) model, we observed a parallel increase in plasma Hcy levels and adverse vascular effects. Moreover, our study unraveled a pivotal role of the CXCL10/CXCR3 axis in Hcy-induced endothelial dysfunction. Hcy exposure led to the upregulation of CXCL10 and CXCR3, both in vitro and in HHcy mice. Importantly, the blockade of this axis, achieved through specific antibodies or NBI-74330, mitigated the detrimental effects of Hcy on endothelial function. In conclusion, our findings illuminated the central role of the CXCL10/CXCR3 axis in mediating Hcy-induced endothelial dysfunction, providing valuable insights for potential therapeutic strategies in managing HHcy-related cardiovascular diseases.
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