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Clinical treatment of TNBC remains challenging, due to the lack of targeted therapies. As TNBC is highly hypoxic with higher HIF-1α expression than other subtypes, we fabricated hypoxia-responsive polymeric micelles co-loading drug and shRNA to treat TNBC by targeting hypoxic tumor microenvironment and subsequently targeting overexpressed HIF-1α under hypoxia. The micelles were assembled from methoxy-polyethylene glycol (mPEG) and poly-L-lysine (PLL) copolymer with AZO as a hypoxia-responsive bridge of mPEG and PLL. Once exposed to hypoxia, AZO bridge was cleaved, resulting in the disassembly of the micelles for rapid release. In vitro and in vivo results showed that the micelles enabled simultaneous delivery of drug and shRNA to hypoxic sites for site-specific rapid release, facilitated by sensitive response to hypoxia; hypoxia-responsive shRNA delivery effectively silenced HIF-1α and its downstream genes, which not only ameliorated the response of hypoxic tumor to drug, but also modulated tumor microenvironment for further improved drug and shRNA delivery; as a result, synergistic treatment of chemotherapy and HIF-1α targeted gene therapy inhibited the growth of primary TNBC tumor and its distant metastasis in a murine model of orthotopic TNBC. Together with their good biocompatibility, hypoxia-responsive polymeric micelles thus emerged as a safe, effective, and universally applicable drug and gene carrier for treatment of TNBC as well as other hypoxic tumors.

Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.

AbstractFungicides are commonly applied through root irrigation in tobacco fields to control soil-borne diseases, and they affect soil microorganisms. However, the effects of metalaxyl-M and hymexazol, used to manage tobacco black shank disease, on these soil microecology remain poorly understood. This study employed high-throughput sequencing technology to explore the soil physical and chemical properties, soil enzyme activity, and the diversity, community structure and function of soil fungi in tobacco fields following root irrigation with metalaxyl-M and hymexazol. The results revealed that ammonium nitrogen (NH4+-N), nitrate nitrogen (NO3--N), soil organic matter (SOM), electrical conductivity (EC) and soil urease (UE) in soil were significantly increased and the pH decreased after root-irrigation with these two fungicides. The abundance of soil fungal community was significantly reduced after the root-irrigation of metalaxyl-M and hymexazol. The relative abundance of Ascomycota increased significantly after the treatment with metalaxyl-M. Following hymexazol treatment, the abundance of Achroiostachys, Nigrospora, Ustilaginoidea, and Trichoderma significantly decreased. Functional prediction analysis indicated an increase in the relative abundance of functional genes of saprophytic fungi after treatment with both fungicides. This study provides a foundational understanding of the environmental behavior and supports the scientific and rational use of metalaxyl-M and hymexazol in soil. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated workplace violence (WPV) toward frontline health workers under comprehensive interventions to improve the occupational safety and health management system in a Chinese infectious disease hospital. Methods: The risk assessment of WPV using an international questionnaire was conducted in 2018 and 2021 to compare the perceived levels of exposure to WPV and intervention measures before and after the intensification of anti-violence measures in the hospital context. Additionally, qualitative data were collected in 2021 through semi-structured and unstructured interviews, providing complementary information about WPV toward frontline health workers (HWs). Results: After establishing the occupational safety and health management system (OSHMS), the total incidence rate of WPV decreased from 60.90% in 2018 to 34.44% in 2021. Psychological violence declined significantly from 60.90% in 2018 to 33.89% in 2021. The endorsement of precautionary measures increased significantly from 2018 to 2021, including patient screening recognition, patient protocol, shift or rota changes, etc. A thematic analysis of several subthemes shows that HWs had an in-depth understanding of WPV, recognizing its multifaceted consequences in the context of complex risk factors. Conclusions: This study demonstrates a significant decrease in WPV, psychological violence, verbal abuse, bullying/mobbing, and ethnic discrimination after implementing the comprehensive OSHMS. [ABSTRACT FROM AUTHOR]

Aim: To investigate the molecular mechanisms underlying memory impairment induced by high‐altitude (HA) hypoxia, specifically focusing on the role of cold‐inducible RNA‐binding protein (CIRP) in regulating the AMPA receptor subunit GluR1 and its potential as a therapeutic target. Methods: A mouse model was exposed to 14 days of hypobaric hypoxia (HH), simulating conditions at an altitude of 6000 m. Behavioral tests were conducted to evaluate memory function. The expression, distribution, and interaction of CIRP with GluR1 in neuronal cells were analyzed. The binding of CIRP to GluR1 mRNA and its impact on GluR1 protein expression were examined. Additionally, the role of CIRP in GluR1 regulation was assessed using Cirp knockout mice. The efficacy of the Tat‐C16 peptide, which consists of the Tat sequence combined with the CIRP 110‐125 amino acid sequence, was also tested for its ability to mitigate HH‐induced memory decline. Results: CIRP was primarily localized in neurons, with its expression significantly reduced following HH exposure. This reduction was associated with decreased GluR1 protein expression on the cell membrane and increased localization in the cytoplasm. The interaction between CIRP and GluR1 was diminished under HH conditions, leading to reduced GluR1 stability on the cell membrane and increased cytoplasmic relocation. These changes resulted in a decreased number of synapses and dendritic spines, impairing learning and memory functions. Administration of the Tat‐C16 peptide effectively ameliorated these impairments by modulating GluR1 expression and distribution in HH‐exposed mice. Conclusion: CIRP plays a critical role in maintaining synaptic integrity under hypoxic conditions by regulating GluR1 expression and distribution. The Tat‐C16 peptide shows promise as a therapeutic strategy for alleviating cognitive decline associated with HA hypoxia. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the dietary views and practices and to identify associated barriers to and facilitators of healthy eating of rural residents emerging from poverty in the context of rapid socio-economic development. A qualitative design with semi-structured interviews was utilized to collect detailed insights into the dietary behaviors of 22 rural residents from 10 villages in Fengshan town, Dafang county, Guizhou province, China. Thematic analysis was applied to interpret the interview data, guided by the socio-ecological model. Four themes were identified: traditional eating patterns, factors influencing food choice, limited knowledge of healthy diet, and lack of nutritional guidance. Barriers to healthy eating included traditional but unhealthy foods, limited nutritional knowledge, inadequate understanding of nutritional requirements, overwhelming nutritional information, and limited professional guidance. Facilitators encompassed healthy traditional eating patterns, household composition, home gardening, preference for traditional bean and soy products, improved food supply and availability owing to poverty alleviation efforts, and being open to receiving professional dietary guidance. As a preliminary investigation into the dietary views and practices of this population, the study highlights a significant gap in the nutritional knowledge and guidance available to rural residents in China, emphasizing the need for comprehensive strategies that address the complex socio-ecological factors influencing dietary behaviors. [ABSTRACT FROM AUTHOR]