1.Study on microwave radiation aggravating the impairment of cognitive functions in mice with experimental periodontitis
ZHOU Hongjin ; WANG Jianhui ; LIU Lin ; LI Hongbo
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(6):541-545
Objective:
To explore the effects of microwave radiation on cognitive function and neuroinflammation in mice with experimental periodontitis, providing experimental evidence for understanding how environmental exposure may be linked to the risk of neurodegenerative diseases by modulating chronic inflammation as a shared pathological mechanism
Methods:
This study was approved by the Animal Ethics Committee of the Academy of Military Medical Sciences. C57BL/6J mice were randomly divided into a control group (C group, untreated), a microwave radiation group (R group, exposed to microwave radiation only), a periodontitis group (P group, ligation-induced periodontitis only), and a periodontitis + microwave radiation group (PR group, ligation-induced periodontitis plus microwave radiation exposure). A periodontitis model was established using the silk ligation method. Eight weeks after modeling, the R and PR groups were subjected to whole-body microwave radiation at 2 800 MHz and 10 mW/cm2 for 10 h/day for 7 consecutive days. Behavioral tests were conducted: the open field test and elevated plus maze test were used to assess anxiety-like behavior, the Y-maze test to evaluate spatial memory, and the novel object recognition test to assess learning and memory abilities. Micro-CT, hematoxylin & eosin staining (HE), and quantitative real-time polymerase chain reaction (qPCR) were used to analyze periodontal tissue pathology and local inflammation. Serum and brain levels of lipopolysaccharide (LPS), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA). The composition of the oral microbiota was analyzed based on 16S rRNA sequencing.
Results:
Behavioral tests showed that anxiety-like behavior was significantly exacerbated in the R and PR groups, and spatial and recognition memory impairments in the PR and P groups were more severe compared with the R and C groups, respectively (P < 0.05). Histological and molecular biological analyses revealed that periodontal inflammation infiltration, alveolar bone resorption, and local expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were further exacerbated in the PR and P groups compared with the R and C groups, respectively (P < 0.05). ELISA results showed that in serum, LPS levels in group P and group PR were increased compared with group C and group R, respectively. The levels of TNF-α, IL-1β, and IL-6 in group PR were significantly higher than those in group P and group R, with a synergistic increase in TNF-α level (P < 0.05). In brain tissue, LPS and TNF-α, IL-1β, IL-6 levels in group P were significantly higher than those in group C; all the above indicators in group PR were significantly higher than those in group P and group R, and LPS and IL-6 levels showed a synergistic increase (P < 0.05). Oral microbiota analysis found that microwave radiation further reduced microbial diversity on the basis of periodontitis, leading to increased relative abundances of Lactobacillus and Enterococcus, and decreased relative abundances of Staphylococcus. Correlation analysis confirmed that these differential bacterial genera were positively correlated with brain inflammation levels and negatively correlated with cognitive function indicators.
Conclusion
Microwave radiation exposure can exacerbate cognitive impairment in mice with experimental periodontitis, and its mechanism may be related to aggravated local periodontal damage, disruption of oral microbiota homeostasis, and subsequent induction of systemic and central neuroinflammatory cascades.
2.Influencing Factors of Depression in Patients with Postoperative Ovarian Cancer
Jialiang YAO ; Long ZHANG ; Jianhui TIAN ; Ze LIU ; Yun YANG ; Yiyang ZHOU ; Minghua LI ; Wang YAO ; Wenfei SHI ; Xinyi LU ; Pan YU ; Enchao CONG
Cancer Research on Prevention and Treatment 2026;53(5):349-359
Objective To explore the prevalence of depressive symptoms in postoperative patients with ovarian cancer and to analyze its influencing factors from multiple dimensions, including clinical characteristics, psychological factors, and laboratory indicators. Methods A cross-sectional study was conducted, which enrolled 235 postoperative patients with ovarian cancer. Depressive status was assessed using the patient health questionnaire, and the demographic, pathological, and medical record data of the patients were collected using the generalized anxiety disorder scale, Pittsburgh sleep quality index, European organization for research and treatment of cancer quality of life questionnaire core 30, and ECOG performance status score. Peripheral blood tumor marker (CA125), routine blood test, lymphocyte subsets, and serum cytokine levels were measured. Univariate and multivariate binary logistic regression analysis were used for statistical analysis. Results The prevalence of depression in postoperative patients with ovarian cancer was 39.15% (92/235). Univariate analysis showed that ECOG score ≥ 2 points, pain, anxiety, poor sleep quality, low quality of life, low life satisfaction, tumor recurrence, six or more cycles of chemotherapy, as well as higher levels of CA125, NLR, and NAR, and lower hemoglobin levels were significantly associated with depression (all P<0.05). Multivariate binary Logistic regression analysis showed that anxiety (OR=1.975, 95%CI: 1.231-3.170), sleep efficiency (OR=4.181, 95%CI: 1.211-14.43), sleep latency (OR=34.806, 95%CI: 4.258-284.542), ECOG performance status score, cognitive function (OR=0.918, 95%CI: 0.868-0.97), and life satisfaction were independent risk factors for depression (all P<0.05). Laboratory indicators were not independent influencing factors in the multivariate Logistic regression model. Conclusion Depression in postoperative patients with ovarian cancer is influenced by physiological, psychological, and social factors. Clinical management should focus on patients with anxiety, sleep disorders, poor physical condition, and low life satisfaction, and a comprehensive prevention and treatment strategy centered on psychological intervention and taking into account symptom management and social support should be implemented.
3.Dosimetric comparison and analysis of AXB and AAA algorithms in postoperative radiotherapy planning for left-sided breast cancer after breast-conserving surgery
Jianhui WU ; Yufeng GAO ; Kai GAO ; Chengqiong TANG ; Jiao LIU
Chinese Journal of Radiological Health 2026;35(1):120-127
Objective To investigate the impact of two different algorithms, AAA and AXB, on the dose distribution of postoperative radiotherapy for left-sided breast cancer after breast-conserving surgery. Methods A total of 96 target volumes from patients who underwent breast-conserving surgery for left-sided breast cancer were selected for dose verification using a two-dimensional matrix system. The planned dose distributions were simulated using both AAA and AXB algorithms. Dosimetric differences in organs at risk and the target volumes were then compared to identify the algorithm that could reduce the radiation dose to organs at risk without compromising the dose distribution to the target volume. Dose verification was performed on the plans generated by both algorithms, and the pass rates of plans for each target volume using both algorithms were compared to provide a quantitative basis for the precise selection of subsequent radiotherapy plans. Results Both AAA and AXB plans met the radiotherapy requirements. The AXB algorithm demonstrated significant advantages in the D98, D2, homogeneity index, and conformity index for the planning target volume, as well as in the V5 and V20 for the left lung. The AXB algorithm showed advantages in the V30 for the heart and the maximum and mean doses for the skin. With the 2 mm/2% criterion in dose verification, the gamma pass rate was higher for the AXB algorithm. Conclusion Through a comparative analysis of the two algorithms, this study revealed that the AXB algorithm offers certain advantages in the dose distribution of radiotherapy after breast-conserving surgery for left-sided breast cancer. These findings provide an important reference for the rational selection of algorithms in clinical practice and are expected to improve radiotherapy efficacy and patient prognosis.
4.Analysis of risk factors for allogeneic blood transfusion and construction of a prediction model in patients with ovarian cancer undergoing cytoreductive surgery
Jia CAO ; Wenyan CHEN ; Panpan MA ; Jin ZHAO ; Hongyue TANG ; Jianhui LIU ; Ruili GENG
Chinese Journal of Blood Transfusion 2026;39(8):1026-1032
Objective: To explore the independent risk factors of allogeneic blood transfusion during perioperative period of cytoreductive surgery in patients with ovarian cancer, and to construct a predictive model to facilitate clinical risk assessment and optimize perioperative blood management. Methods: Clinical data of 156 patients who underwent cytoreductive surgery for ovarian cancer in our hospital from January 2020 to December 2025 were retrospectively collected. The patients were divided into transfusion group (n=51) and non-transfusion group (n=105) according to whether they received allogeneic blood transfusion during perioperative period. The 1∶1 propensity score matching (PSM) was used to correct the confounding factors. Independent sample t test or Mann-Whitney U test was used for measurement data, and chisquare test was used for enumeration data. Variables with P<0.05 in univariate analysis were included in binary logistic regression for multivariate analysis to determine independent risk factors. A nomogram model for perioperative allogeneic blood transfusion risk prediction was constructed based on independent risk factors. Bootstrap method (100 samples) was used for internal calibration verification. ROC curve was used to evaluate the discrimination efficiency, and decision curve analysis (DCA) was used to evaluate the clinical net benefit of the model. Results: After propensity matching, the baseline data of the two groups were balanced and comparable. Multivariate logistic regression analysis showed that preoperative prothrombin time (PT) (OR=2.666, 95%CI 1.249~5.693, P=0.011), preoperative hemoglobin (Hb) (OR=0.953, 95%CI 0.923~0.984, P=0.003), intraoperative blood loss (OR=1.004, 95%CI 1.001-1.006, P=0.004), preoperative anemia grade (OR=3.052, 95%CI 1.007-9.252, P=0.049) were independent influencing factors of perioperative allogeneic blood transfusion. The nomogram model based on the above four factors was significant (LR χ
=58.617, P<0.001), and the internal calibration curve showed that the predicted probability of the model was in good agreement with the actual probability (mean absolute error=0.042). The area under the ROC curve (AUC) was 0.890, indicating good discrimination efficiency. DCA showed that the clinical net benefit of the model was better than that of the unified transfusion/non-transfusion strategy in the 0-0.45 risk threshold range. Conclusion: Intraoperative blood loss, preoperative PT, preoperative Hb and preoperative anemia grade are independent risk factors for perioperative allogeneic blood transfusion in patients undergoing cytoreductive surgery for ovarian cancer. The nomogram model based on the above factors has good predictive efficacy and clinical hierarchical decision-making value, which can provide reference for clinical implementation of individualized blood management for high-risk patients and reduction of unnecessary blood transfusion rate.
5.Peripheral Immune Response Patterns Under Vital Qi-Strengthening and Toxin-Eliminating Therapy and Their Value in Assessing Vital Qi Deficiency in Lung Cancer Metastasis: A Group-Based Trajectory Modeling
Fan XU ; Jianhui TIAN ; Yuan YAO ; Zhenyang CHENG ; Yanhong WANG ; Bin LUO ; Jialiang YAO ; Wang YAO ; Xinyi LU ; Yuchen BAO ; Xiaoyu YANG ; Youjun LIU ; Yiyang ZHOU ; Jianchun WU ; Minghua LI ; Wenfei SHI ; Yajing CUI ; Qingzhong LIU ; Yan LI ; Yun YANG
Cancer Research on Prevention and Treatment 2026;53(9):711-717
Objective On the basis of the theory of the tumor metastatic state, this work aims to explore the metastasis trajectories and peripheral immune response patterns in patients with non-small cell lung cancer (NSCLC) receiving vital qi-strengthening and toxin-eliminating therapy (Fuzheng Juandu) and reveal the value of peripheral immunity in assessing vital qi deficiency during metastasis. Methods A retrospective study design was adopted. Patients with NSCLC admitted from January 1, 2018, to October 31, 2025 were enrolled. Data on metastasis status and peripheral immune indices were collected at the follow-up time points of one, two, three, and five years. Group-based trajectory modeling was used to fit metastasis trajectories, and the independent predictors of trajectory grouping were analyzed through multifactor and multiclassification logistic regression. Results A total of 184 patients with NSCLC were included, and three different groups of metastasis trajectories were identified, namely, the low-risk stable (46.74%, n=86), low-risk rising (13.59%, n=25), and high-risk stable (39.67%, n=73) groups. Univariate analysis revealed substantial differences in peripheral immune indices among the three trajectory groups. Multivariate analysis showed that TNM stage, absolute neutrophil count, lymphocyte count, absolute monocyte count, platelet volume, SAA:CRP ratio, and NLR were independent predictors of the low-risk rising group, whereas TNM stage, absolute monocyte count, basophil count, SII, and NLR were independent predictors of the high-risk stable group. Conclusion Under Fuzheng Juandu therapy, patients with NSCLC exhibit three distinct metastasis trajectories, each
6.Huashi Baidu Granules Treat Influenza Viral Pneumonia by Regulating Gut-Lung Axis
Qijing LI ; Hanhui HUANG ; Yurong DENG ; Ao'ao WANG ; Jianliang LI ; Jianhui SUN ; Liyu HAO ; Zongyuan LI ; Guimin LIU ; Hongmei LI ; Luqi HUANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(23):59-69
ObjectiveTo explore the mechanism of Huashi Baidu granules in treating influenza A (H1N1) virus infection based on the gut-lung axis. MethodsBALB/c mice were randomly assigned into a blank control group, a model control group, a positive control (oseltamivir phosphate capsules, 19.5 mg·kg-1) group, and a Huashi Baidu granules (17.81 g·kg-1) group. Mice in other groups except the blank control group were instilled nasally by H1N1 viral fluid for the modeling of influenza viral pneumonia and treated with corresponding drugs once daily by gavage for 5 consecutive days. The mouse lung index was calculated, and pathological changes in the lung and colon tissue were observed. Western blot was employed to quantify the expression levels of nucleotide-binding oligomeric domain-like receptor protein 3 (NLRP3), cysteinyl aspartate-specific proteinase -1 (Caspase-1), apoptosis-associated Speck-like protein containing a CARD (ASC), gasdermin D (GSDMD), interleukin-18 (IL-18), IL-1β, and colonic tight junction protein 1 (CLDN1), and Occludin in the lung and colon tissue. Non-targeted metabolomics was employed to analyze the metabolic profiles of the lung tissue and intestinal contents. The 16S rRNA sequencing was performed to analyze the gut microbiota structure in intestinal contents. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the 5-hydroxytryptamine (5-HT) levels in the serum, lung tissue, and colon tissue. ResultsCompared with the blank control group, the model control group showed elevated lung index, marked inflammatory cell infiltration and alveolar structural destruction in the lung tissue, obvious inflammatory cell infiltration and mucosal epithelial damage in the colon tissue, upregulated protein levels of NLRP3 inflammasome pathway proteins NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18 in the lung and colon tissue (P<0.05, P<0.01), downregulated protein levels of CLDN1 and Occludin in the colon tissue (P<0.05, P<0.01). Compared with the model control group, Huashi Baidu Granules reduced the lung index (P<0.01), alleviated pathological damage in the lungs and colon, inhibited the expression of NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18 in lung and colon tissue (P<0.05, P<0.01), and upregulated the expression of CLDN1 and Occludin in the colon tissue (P<0.05, P<0.01). Metabolomics analysis showed that Huashi Baidu Granules downregulated the 5-HT pathway and arachidonic acid metabolism pathway in the lung and colon tissue, while upregulating nucleotide metabolism and TCA cycle. Compared with the blank control group, the model control group exhibited elevated levels of 5-HT in the serum, lung tissue, and colon tissue (P<0.01). The intervention with Huashi Baidu Granules lowered the levels of 5-HT in the serum (P<0.05) and the lung and colon tissue (P<0.01). Huashi Baidu Granules increased the diversity of gut microbiota, enriched beneficial bacteria such as Blautia, and inhibited pathogenic bacteria such as Desulfovibrio. ConclusionHuashi Baidu Granules significantly alleviate lung inflammation and pathological damage in mice infected with influenza A (H1N1) virus, reshape the intestinal microecology, and repair the intestinal barrier. It may exert cross-organ regulation by inhibiting the cascade of "gutogenic 5-HT release-circulatory transport-pulmonary 5-HT receptor activation-NLRP3 inflammasome assembly." It exerts therapeutic effects on influenza viral pneumonia through the gut-lung axis. This study provides a modern biological interpretation for the TCM theories of interior-exterior relationship between the lung and large intestine and simultaneous treatment of the lung and intestine.
7.TSZAF monomer combination downregulates the Wnt/β-catenin signaling pathway and inhibits neutrophil recruitment to prevent lung cancer metastasis.
Pan YU ; Jialiang YAO ; Long ZHANG ; Yanhong WANG ; Xinyi LU ; Jiajun LIU ; Zujun QUE ; Yao LIU ; Qian BA ; Jiwei LIU ; Yan WU ; Jianhui TIAN
Chinese Journal of Natural Medicines (English Ed.) 2025;23(9):1069-1079
Metastasis remains the primary cause of cancer-related mortality worldwide. Circulating tumor cells (CTCs) represent critical targets for metastasis prevention and treatment. Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity. Tiao-Shen-Zhi-Ai Formular (TSZAF) represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment. This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination (TSZAF mc) to investigate its anti-metastatic effects and mechanisms. TSZAF mc demonstrated significant inhibition of proliferation, migration, and invasion in CTC-TJH-01 and LLC cells, while inducing cellular apoptosis in vitro. Moreover, TSZAF mc substantially inhibited LLC cell growth and metastasis in vivo. Mechanistically, TAZSF mc significantly suppressed the Wnt/β-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues. Additionally, TAZSF mc notably reduced neutrophil infiltration in metastatic lesions. These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/β-catenin signaling pathway and reducing CXCL5 secretion, thereby decreasing neutrophil recruitment and infiltration. TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.
Lung Neoplasms/genetics*
;
Wnt Signaling Pathway/drug effects*
;
Animals
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Humans
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Drugs, Chinese Herbal/pharmacology*
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Mice
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Neoplasm Metastasis/prevention & control*
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Cell Proliferation/drug effects*
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Cell Line, Tumor
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Neutrophil Infiltration/drug effects*
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Down-Regulation/drug effects*
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Cell Movement/drug effects*
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beta Catenin/genetics*
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Apoptosis/drug effects*
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Mice, Inbred C57BL
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Male
;
Neoplastic Cells, Circulating/drug effects*
8.Research progress on treatment of pleural effusion related to immune checkpoint inhibitors
Tianqi AN ; Jianhui TIAN ; Yiyang ZHOU ; Bin LUO ; Zujun QUE ; Yao LIU ; Pan YU ; Ruihua ZHAO ; Yun YANG
China Oncology 2025;35(3):333-338
Immunotherapy for cancer,as an emerging treatment modality,has made significant strides in recent years and has become a crucial therapeutic approach following surgery,radiotherapy,chemotherapy,and targeted therapy.In particular,the clinical utilization of immune checkpoint inhibitors(ICIs)has not only enhanced the survival rates of patients with refractory or recurrent tumors but has also significantly optimized the overall strategy for cancer treatment.However,as the population undergoing cancer immunotherapy continues to grow,this expansion not only yields clinical benefits but also precipitates a range of specific adverse reactions known as immune-related adverse events(irAEs).Pleural effusion is a common and severe complication in cancer patients,significantly affecting both their quality of life and treatment outcomes.Typically,tumor-related pleural effusion is often due to pleural metastasis,with malignant pleural effusion(MPE)characterized by rapid growth,being difficult to control,and tendency for recurrence.With the approval of new drugs and the expansion of indications for existing medications,the number of cancer patients receiving ICIs treatment is increasing,bringing ICIs-related pleural effusion into focus.While ICIs treatment-related pleural effusion is relatively rare in clinical practice,it is closely linked to treatment choices of patients and prognosis.Unlike MPE,the pathogenesis of ICIs treatment-related pleural effusion is more complex,not only involving non-specific immune activation leading to autoimmune inflammatory reactions but also potentially related to nodular pleural granulomatous reactions,eosinophilic chronic pleurisy,and tumor-infiltrating lymphocytes.In terms of diagnosis,ICIs treatment-related pleural effusion is typically diagnosed through exclusion,requiring the exclusion of other causes such as tumor progression,radiotherapy,and chemotherapy-induced pleural effusion,adding complexity and difficulty to the diagnostic process.Treatment for ICIs treatment-related pleural effusion often involves glucocorticoids,tocilizumab,or infliximab,aiming to alleviate symptoms and improve prognosis by suppressing excessive immune reactions.Preventing the occurrence of ICIs treatment-related pleural effusion is equally crucial,necessitating comprehensive patient assessment before ICIs administration and continuous monitoring during treatment to promptly detect and manage potential adverse reactions.Through this comprehensive management approach,the impact of ICIs treatment-related pleural effusion on patient quality of life and treatment outcomes can be minimized,optimizing overall treatment results.This review aimed to explore the pathogenesis,histological features,clinical manifestations,diagnostic methods and treatment strategies of ICIs treatment-related pleural effusion,and delve into the characteristics of ICIs treatment-related pleural effusion,in order to enhance understanding of this complication and provide a reference for clinical practice.
9.Study on the brain functional network and structural-functional coupling in children with drug-resistant epilepsy
Xuhong LI ; Jianhui XIAO ; Heng LIU ; Yulun HE ; Haifeng RAN ; Yuxin XIE ; Guiqin CHEN ; Qian′e YU ; Zhen ZENG ; Wenfu LI ; Tijiang ZHANG
Chinese Journal of Radiology 2025;59(2):184-191
Objective:To investigate the changes in brain functional network and structural-functional network coupling in children with drug-resistant epilepsy (DRE), and to analyze their correlation with cognitive function, disease duration, and age of onset.Methods:This study was a cross-sectional study. Clinical and imaging data of 19 children with DRE who received consultation and treatment at the Affiliated Hospital of Zunyi Medical University from August 2021 to August 2023 (DRE group) were prospectively included. Another 27 age-and sex-matched healthy children were collected as the healthy control group. All subjects had 3D-T 1WI, T 2 fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) scans and Wechsler Intelligence Scale assessments. Independent sample t-test and Mann-Whitney U test were used to analyze the global and local topological attributes, as well as the structural-functional coupling (SFC) values at the whole brain and modular levels in two groups. Correlations between abnormal resting state brain functional network indicators and the Wechsler Intelligence Scale score [verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), processing speed index (PSI), full scale intelligence quotient (FSIQ)], disease duration and age of onset was evaluated using a Spearman or Pearson correlation analysis. Results:Compared to the healthy control group, DRE group exhibited decreased VCI, PRI, WMI, PSI, FSIQ and the differences were all statistically significant (all P<0.05). Both brain functional networks had small world attributes. There was a statistically significant difference in the area under the curve of sparsity of degree centrality (DC) in the left pallidum between the DRE group and healthy control group (2.998±0.942, 4.992±1.945, t=-4.07, FDR corrected P<0.05). Compared with the control group, the DRE group had decreased SFC within the limbic network (LN) ( P<0.05), increased SFC within the sensorimotor (SMN) ( P<0.05), decreased SFC between the default mode network-LN ( P<0.05), and increased SFC between the SMN-attentional network (AN) ( P<0.05). There was no statistically significant difference in SFC at the whole brain level between the two groups. Correlation analysis indicated that DC in left pallidum in DRE group negatively correlated with the PSI ( r=-0.537, P=0.018), and SFC between the SMN and AN demonstrated a negative correlation with age of onset ( r=-0.537, P=0.018). Conclusion:The altered DC in left pallidum may be related to cognitive impairment in children with DRE, providing biomarker information for the study of neural mechanisms in children with DRE.
10.Research progress in therapeutic human papillomavirus vaccines
Pengju YU ; Weijin HUANG ; Weilu LIU ; Jianhui NIE
Chinese Journal of Microbiology and Immunology 2025;45(11):965-973
Cervical cancer is the fourth most prevalent cancer among women worldwide,which is closely related to human papillomavirus(HPV)infection. Since prophylactic HPV vaccines cannot clear established infections,therapeutic HPV vaccines are urgently needed to induce a cytotoxic T cell-dominated immune response to clear HPV infections or improve HPV-related conditions. This article systematically reviews the immune design strategy,research and development platform,and clinical research progress of therapeutic HPV vaccines,aiming to provide ideas for the research and development of therapeutic HPV vaccines.


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