Objective To investigate the effects of Echinococcus multilocularis infection on levels of memory T (Tm) cells and their subsets in lymph nodes of mice at different stages of infection, so as to provide new insights into immunotherapy for alveolarechinococcosis. MethodsTwenty-four C57BL/6J mice aged 6 to 9 weeks were randomly divided into the infection group and the control group, of 12 mice in each group. Mice in the infection group were administered with 3 000 E. multilocularis protoscoleces via portal venous injection, while animals in the control group were administered with an equal volume of physiological saline. Three mice from each group were sacrificed 4, 12 weeks and 24 weeks post-infection, and lymph nodes were sampled and stained with hematoxylin and eosin (HE) to investigate the histopathological changes of mouse lymph nodes in the infection group. The expression and localization of T lymphocyte surface markers CD3, CD4, and CD8 were observed in mouse lymph nodes using immunohistochemical staining. In addition, lymphocyte suspensions were prepared from mouse lymph nodes in both groups at different time points post-infection, and the levels of Tm cell subsets and their secreted cytokines were detected using flow cytometry. Results HE staining showed diffuse structural alterations in the subcapsular cortical and paracortical regions of mouse lymph nodes in the infection group 4 weeks post-infection with E. multilocularis. Immunohistochemical staining detected CD3, CD4 and CD8 expression in mouse lymph nodes in both groups. Flow cytometry revealed higher proportions of CD4⁺ Tm cells [(55.3 ± 4.8)% vs. (38.8 ± 6.1)%; t = -4.259, P < 0.05] and CD4⁺ tissue-resident Tm (Trm) cells [(57.7 ± 3.7)% vs. (34.1 ± 11.2)%; t = -3.990, P < 0.05] in mouse lymph nodes in the infection group than in the control group 4 weeks post-infection, and higher proportions of CD4⁺ Tm cells [(34.6 ± 3.2)% vs. (23.3 ± 7.5)%; t = -2.764, P < 0.05] and CD4⁺ Trm cells [(44.0 ± 1.9)% vs. (31.2 ± 1.5)%; t = -4.039, P < 0.05] in mouse lymph nodes in the infection group than in the control group 24 weeks post-infection. The proportions of CD8⁺ Tm cells were higher in the infection group than in the control group 4 weeks [(56.8 ± 2.7)% vs. (43.9 ± 5.2)%; t = -4.416, P < 0.01] and 12 weeks post-infection [(25.4 ± 2.7)% vs. (12.0 ± 2.6)%; t = -2.552, P < 0.05], while the proportions of tumor necrosis factor (TNF)-α⁺ CD4⁺ T cells [(15.7 ± 5.0)% vs. (49.4 ± 6.4)%; t = 7.150, P < 0.01], TNF-α⁺CD8⁺ T cells [(20.7 ± 5.5)% vs. (57.5 ± 8.4)%; t = -6.694, P < 0.01], and TNF-α⁺ CD8⁺ Tm cells [7.0% (1.0%) vs. 31.0% (11.0%); Z = -2.236, P < 0.05] were lower in the infection group than in the control group 24 weeks post-infection. Conclusions Tm cells levels are consistently increased in lymph nodes of mice at different stages of E. multilocularis infection, with Trm cells as the predominantly elevated subset. The impaired capacity of CD8⁺ Tm cells to secrete the effector molecule TNF-α in mouse lymph nodes at the late-stage infection may facilitate chronic parasitism of E. multilocularis.

ObjectiveTo investigate the prognostic role of radiotherapy in women aged 70 years or older with breast cancer. MethodsA total of 311 women aged 70 years or older with breast cancer undergoing breast-conserving surgery in the Second Affiliated Hospital of Nanchang University between February 28， 2011 and February 28， 2021， were divided into two groups： 183 patients in the control group were given postoperative radiotherapy， and 128 patients in the case group were not treated by radiotherapy. The nonparametric Mann-Whitney U test or χ² test was used to compare the general clinicopathological data of the two groups， the Kaplan-Meier method and log-rank test to analyze the disease-free survival （DFS） and overall survival （OS）， multivariate Cox proportional hazards regression model to examine the factors affecting DFS and OS. Additional subgroup analysis was performed. ResultsThere were no statistically significant differences between the control and case groups in age， T-stage， N-stage， tumor clinical stage， estrogen receptor （ER）， progesterone receptor （PR） and human epidermal growth factor receptor type 2 （HER2） statuses， Ki-67， tumor histological grade， tumor pathological type， and whether they received adjuvant chemotherapy or postoperative endocrine therapy （all P > 0.05）. The median follow-up was 110.0 （95%CI： 98.9， 121.1） months for the control group and 93.0 （95% CI： 86.1， 100.0） months for the case group. Differences between the two groups in DFS rate were significant （92.9% vs. 85.2%， P = 0.024）， but in OS rate insignificant （92.3% vs. 88.3%， P=0.199）. Multivariate Cox proportional hazards regression analysis showed that T-stage， N-stage （N2 and N3）， HER2 status， Ki-67， tumor histological grade （grade Ⅱ and Ⅲ）， and no radiotherapy were independent risk factors for DFS in elderly breast cancer patients （all P < 0.05）， while ER status was an independent protective factor （P < 0.05）. The independent risk factors for OS in elderly breast cancer patients included tumor stage， N-stage （N2 and N3）， HER2 status， and Ki-67 （all P < 0.05）， and ER status was an independent protective factor （P < 0.05）. Subgroup analysis revealed that in elderly hormone receptor （HR）-negative breast cancer patients， the median follow-ups of the control and case groups were 123.0 （95% CI： 116.8， 129.2） months and 88.0 （95% CI： 75.2， 100.8） months， respectively， with a statistically significant difference both in DFS （91.3% vs. 68.6%， P=0.008） and OS rates （89.1% vs. 71.4%， P=0.027）. ConclusionsPost-breast-conserving radiotherapy provides a limited survival benefit in the overall elderly breast cancer patients， but a significant survival benefit in the elderly HR-negative breast cancer patients， which suggests the need for a prospective randomized controlled trial of a stratified step-down strategy for radiotherapy in elderly breast cancer patients.

BACKGROUND: Regulatory dendritic cell (DCreg) subset exhibits a unique capacity for inducing immune tolerance among the variety subsets of dendritic cells (DCs) within gut-associated lymphoid tissues (GALTs). Fms-like tyrosine kinase 3 ligand (FLT3L) is involved in the differentiation of DCregs and the subsequent expansion of regulatory T-cells (Tregs) mediated by DCregs, though the precise mechanism remains poorly understood. This study aimed to explore the expansion mechanism of Treg induced by DCreg and the role of FLT3L in this process. METHODS: DCregs were distinguished from other DC subsets isolated from GALTs of BALB/c mice through a mixed lymphocyte reaction assay. The functions and mechanisms by which FLT3L promoted Treg expansion via DCregs were investigated in vitro through co-culture experiments involving DCregs and either CD4 + CD25 - T-cells or CD4 + CD25 + T-cells. Additionally, an in vivo experiment was conducted using a dextran sulfate sodium (DSS)-induced colitis model in mice. RESULTS: CD103 + CD11b + DC exhibited DCreg-like functionality and was identified as DCreg for subsequent investigation. Analysis of Foxp3 + Treg percentages within a co-culture system of CD4 + CD25 - T-cells and DCregs, with or without FLT3L, demonstrated the involvement of the FLT3/FLT3L axis in driving the differentiation of precursor T-cells into Foxp3 + Tregs induced by DCregs. Cell migration and co-culture assays revealed that the FLT3/FLT3L axis enhanced DCreg migration toward Tregs via the Rho pathway. Additionally, it was observed that DCregs could promote Treg proliferation through the Notch pathway, as inhibition of Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) suppressed Treg expansion within the co-culture system of DCregs and CD4 + T-cells or CD4 + CD25 + T-cells. Furthermore, the FLT3/FLT3L axis influenced JAG1 expression in DCregs, indirectly modulating Treg expansion. In vivo experiments further established that FLT3L promoted DCreg expansion and restored Treg balance in DSS-induced colitis models, thereby ameliorating colitis symptoms in mice. CONCLUSION The FLT3/FLT3L axis is integral to the maintenance of DCreg function in Treg expansion.
Animals ; T-Lymphocytes, Regulatory/immunology* ; Dendritic Cells/immunology* ; Mice ; Mice, Inbred BALB C ; Membrane Proteins/metabolism* ; Receptors, Notch/metabolism* ; Lymphoid Tissue/metabolism* ; Signal Transduction/physiology* ; Coculture Techniques ; Flow Cytometry

Alzheimer's disease (AD), a prototypical neurodegenerative disorder, encompasses multifaceted pathological processes. As pivotal cellular structures within the central nervous system, ion channels play critical roles in regulating neuronal excitability, synaptic transmission, and neurotransmitter release. Extensive research has revealed significant alterations in the expression and function of ion channels in AD, implicating an important role of ion channels in the pathogenesis of abnormal Aβ deposition, neuroinflammation, oxidative stress, and disruptions in calcium homeostasis and neural network functionality. This review systematically summarizes the crucial roles and underlying mechanisms of ion channels in the onset and progression of AD, highlighting how these channel abnormalities contribute to AD pathophysiology. We also discuss the therapeutic potential of ion channel modulation in AD treatment, emphasizing the importance of addressing multifactorial nature and heterogeneity of AD. The development of multi-target drugs and precision therapies is proposed as a future direction of scientific research.
Alzheimer Disease/therapy* ; Humans ; Ion Channels/physiology* ; Oxidative Stress ; Animals ; Amyloid beta-Peptides/metabolism* ; Synaptic Transmission ; Calcium/metabolism*

Salivary gland tumor is one of the most common tumors in oral and maxillofacial regions. The diagnosis and treatment of salivary gland tumors had been a clinical characteristic project in Peking University School and Hospital of Stomatology since long time ago. Here we introduced the research progress in diagnosis and treatment of salivary gland tumors during the past 10 years. Among 7 190 cases of salivary gland tumors treated in this institution, 4 654 cases (64.7%) were benign, and 2 536 (35.3%) were malignant, with benign ∶ malignant ratio of 1.84 ∶ 1. Parotid was the most common location, followed by minor salivary gland and submandibular gland, while sublingular gland tumor was seldom seen. The proportion of minor salivary gland tumor was relatively high. Among 1 874 cases with primary malignant tumors, the cases with T3 and stage Ⅲ accounted for only 9.6% and 10.3%, respectively, which indicated that there was shortcoming in the T classification and clinical stage formulated by Union for International Cancer Control (UICC), and further revision was required. The 5, 10, and 15 year survival rates of 1 637 cases with postoperative follow-up were 93.1%, 87.2% and 79.3%, respectively, which were much higher than those we reported 30 years ago. The improvement of treatment results was related to more widely used combined treatment with surgery and postoperative radiotherapy, and the increase in patients with early stage. Adenoid cystic carcinoma was the malignant tumor with high rate of distant metastasis. The 5 and 10 year survival rates of the patients with pulmonary metastasis were 76.2% and 51.8%, respectively, which indicated that the pulmonary metastatic carcinomas developed slowly. Recurrent rate of carcinoma ex pleomorphic adenoma was 46.7% after single treatment of sur-gery, while it decreased to 27.5% after combined theraphy with surgery and radiotherapy, indicating that postoperative radiotheraphy could reduce the recurrent rate effectively. The normal myoepithelial cells had the inhibiting role in the invasion and metastasis of carcinoma ex pleomorphic adenoma. The evaluation of integrity of myoepithelial cells surrounding the tumor mass is helpful to understand the invasiveness of the tumors. The new surgical modalities such as extracapsular resection and partial sialoadenectomy were used in treatment of benign tumors of parotid gland and submandibular gland with advantages of decreased tissue damage and preservation of glandular function. Application of digital surgical techniques such as mixed reality combined with surgical navigation and real-time three-dimensional holograms in the surgical treatment of parotid gland tumors showed the benifits of more safety and precision, and less tissue da-mage.
Humans ; Salivary Gland Neoplasms/pathology* ; Carcinoma, Adenoid Cystic/therapy* ; Adenoma, Pleomorphic/therapy* ; Neoplasm Staging

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

Personalized drug response prediction from molecular data is an important challenge in precision medicine for treating cancer. Computational methods have been widely explored and have become increasingly accurate in recent years. However, the clinical application of prediction methods is still in its infancy due to large discrepancies between preclinial models and patients. We present a novel disentangled synthesis transfer network (DiSyn) for drug response prediction specifically designed for transfer learning from preclinical models to clinical patients. DiSyn uses a domain separation network (DSN) to disentangle drug response related features, employs data synthesis technology to increase the sample size and iteratively trains for better feature disentanglement. DiSyn is pretrained on large-scale unlabeled cancer samples and validated by three datasets, The Cancer Genome Atlas (TCGA), Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2 (I-SPY2) and Novartis Institutes for Biomedical Research Patient-Derived Xenograft Encyclopedia (NIBR PDXE), achieving competitive performance with the state-of-the-art methods on cancer patients and mice. Furthermore, the application of DiSyn to thousands of breast cancer patients show the heterogeneity in drug responses and demonstrate its potential value in biomarker discovery and drug combination prediction.