Search

Abstract Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.

Abstract Currently, the relationship between household size and incident dementia, along with the underlying neurobiological mechanisms, remains unclear. This prospective cohort study was based on UK Biobank participants aged ≥ 50 years without a history of dementia. The linear and non-linear longitudinal association was assessed using Cox proportional hazards regression and restricted cubic spline models. Additionally, the potential mechanisms driven by brain structures were investigated by linear regression models. We included 275,629 participants (mean age at baseline 60.45 years [SD 5.39]). Over a mean follow-up of 9.5 years, 6031 individuals developed all-cause dementia. Multivariable analyses revealed that smaller household size was associated with an increased risk of all-cause dementia (HR, 1.06; 95% CI 1.02–1.09), vascular dementia (HR, 1.08; 95% CI 1.01–1.15), and non-Alzheimer’s disease non-vascular dementia (HR, 1.09; 95% CI 1.03–1.14). No significant association was observed for Alzheimer’s disease. Restricted cubic splines demonstrated a reversed J-shaped relationship between household size and all-cause and cause-specific dementia. Additionally, substantial associations existed between household size and brain structures. Our findings suggest that small household size is a risk factor for dementia. Additionally, brain structural differences related to household size support these associations. Household size may thus be a potential modifiable risk factor for dementia.

Abstract Immobilization of graphene quantum dots (GQDs) on a solid support is crucial to prevent GQDs from aggregation in the form of solid powder and facilitate the separation and recycling of GQDs after use. Herein, spatially dispersed GQDs are post-synthetically coordinated within a two-dimensional (2D) and water-stable zirconium-based metal–organic framework (MOF). Unlike pristine GQDs, the obtained GQDs immobilized on 2D MOF sheets show photoluminescence in both suspension and dry powder. Chemical and photoluminescent stabilities of MOF-immobilized GQDs in water are investigated, and the use of immobilized GQDs in the photoluminescent detection of copper ions is demonstrated. Findings here shed the light on the use of 2D MOFs as a platform to further immobilize GQDs with various sizes and distinct chemical functionalities for a range of applications.

C16H14N2O3, monoclinic, P21/n (no. 14), a = 4.9621(10) Å, b = 11.828(2) Å, c = 23.727(5) Å, β = 94.527(4)°, V = 1388.2(5) Å3, Z = 4, Rgt(F) = 0.0551, wRref(F2) = 0.1847, T = 296(2) K.

Teachers' professional identity has an important impact on the career development of university teachers. The returnee teachers have both domestic and overseas study experience, so they show particularity in professional identity in China. This study adopted the mixed-methods approach to investigate returnee teachers' professional identity and the influencing factors. In the quantitative part, it took some returnee teachers from universities in China as samples, and in the qualitative part, it carried out one-to-one interviews with 8 returnee teachers. The results showed that the overall level of professional identity of returnee teachers was relatively high. Specifically, returnee teachers had the highest degree of identity in professional behavior inclination and the lowest degree of identity in the sense of occupational belonging. Besides, we found the professional identity of returnee teachers was affected by professional emotion, professional ability, professional expectation, professional environment and material conditions. Among them, material conditions and professional environment have greater influence on the professional identity level of returned teachers. We discuss the implications of these findings for research and practice in an educational context.

Abstract Treatment is challenging due to the heterogeneity of hepatocellular carcinoma (HCC). Chromatin regulators (CRs) are important in epigenetics and are closely associated with HCC. We obtained HCC-related expression data and relevant clinical data from The Cancer Genome Atlas (TCGA) databases. Then, we crossed the differentially expressed genes (DEGs), immune-related genes and CRs to obtain immune-related chromatin regulators differentially expressed genes (IRCR DEGs). Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to select the prognostic gene and construct a risk model for predicting prognosis in HCC, followed by a correlation analysis of risk scores with clinical characteristics. Finally, we also carried out immune microenvironment analysis and drug sensitivity analysis, the correlation between risk score and clinical characteristics was analyzed. In addition, we carried out immune microenvironment analysis and drug sensitivity analysis. Functional analysis suggested that IRCR DEGs was mainly enriched in chromatin-related biological processes. We identified and validated PPARGC1A, DUSP1, APOBEC3A, AIRE, HDAC11, HMGB2 and APOBEC3B as prognostic biomarkers for the risk model construction. The model was also related to immune cell infiltration, and the expression of CD48, CTLA4, HHLA2, TNFSF9 and TNFSF15 was higher in high-risk group. HCC patients in the high-risk group were more sensitive to Axitinib, Docetaxel, Erlotinib, and Metformin. In this study, we construct a prognostic model of immune-associated chromatin regulators, which provides new ideas and research directions for the accurate treatment of HCC.