Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Cold tumors have a poor response to tumor immunotherapy due to low immune cell infiltration and the ability to evade immune attacks. Converting cold tumors into hot tumors can enhance the clinical effectiveness of anti-tumor immunotherapy. High-intensity focused ultrasound (HIFU) as a non-invasive treatment can damage tumors through mechanical effects, but there is a lack of research on its cytotoxic mechanisms at the cellular level and its role in inducing anti-immune responses. In this study, the role of HIFU in triggering tumor ferroptosis by disrupting the GSH/GSSG balance through mechanochemical action and the associated anti-tumor immune priming effect were investigated. The use of a nano-enhancer loaded with PFOB combined with HIFU could enhance ferroptosis in triple-negative breast cancer at a specific stage of tumor growth (UTGR = 0) while promoting the conversion of a cold tumor into a hot tumor, thereby improving the immune response. Overall, this provides valuable guidance for the clinical application of HIFU in tumor immunotherapy.

OBJECTIVE: To investigate the application value of pediatric sepsis-induced coagulation (pSIC) score and mean platelet volume/platelet count (MPV/PLT) ratio in the diagnosis of pediatric sepsis and the determination of critical pediatric sepsis. METHODS: A retrospective cohort study was conducted, selecting 112 children with sepsis (sepsis group) admitted to pediatric intensive care unit (PICU) of Liaocheng Second People's Hospital from January 2020 to December 2023 as the study objects, and 50 children without sepsis admitted to the pediatric surgery department of our hospital during the same period for elective surgery due to inguinal hernia as the control (control group). The children with sepsis were divided into two groups according to the pediatric critical case score (PCIS). The children with PCIS score of ≤ 80 were classified as critically ill group, and those with PCIS score of > 80 was classified as non-critically ill group. pSIC score, coagulation indicators [prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen (FIB)], and platelet related indicators (PLT, MPV, and MPV/PLT ratio) were collected. Pearson correlation method was used to analyze the correlation between pSIC score and MPV/PLT ratio as well as their correlation with coagulation indicators. Multivariate Logistic regression analysis was used to screen the independent risk factors for pediatric sepsis and critical pediatric sepsis. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the application value of the above independent risk factors on the diagnosis of pediatric sepsis and the determination of critical pediatric sepsis. RESULTS: 112 children with sepsis and 50 children without sepsis were enrolled in the final analysis. pSIC score, PT, INR, APTT, FIB, MPV, and MPV/PLT ratio in the sepsis group were significantly higher than those in the control group [pSIC score: 0.93±0.10 vs. 0.06±0.03, PT (s): 14.76±0.38 vs. 12.23±0.15, INR: 1.26±0.03 vs. 1.06±0.01, APTT (s): 40.08±0.94 vs. 32.47±0.54, FIB (g/L): 3.51±0.11 vs. 2.31±0.06, MPV (fL): 8.86±0.14 vs. 7.62±0.11, MPV/PLT ratio: 0.037±0.003 vs. 0.022±0.001, all P < 0.01], and PLT was slightly lower than that in the control group (×10⁹/L: 306.00±11.01 vs. 345.90±10.57, P > 0.05). Among 112 children with sepsis, 46 were critically ill and 66 were non-critically ill. pSIC score, PT, INR, APTT, MPV, and MPV/PLT ratio in the critically ill group were significantly higher than those in the non-critically ill group [pSIC score: 1.74±0.17 vs. 0.36±0.07, PT (s): 16.55±0.80 vs. 13.52±0.23, INR: 1.39±0.07 vs. 1.17±0.02, APTT (s): 43.83±1.72 vs. 37.77±0.95, MPV (fL): 9.31±0.23 vs. 8.55±0.16, MPV/PLT ratio: 0.051±0.006 vs. 0.027±0.001, all P < 0.05], PLT was significantly lower than that in the non-critically ill group (×10⁹/L: 260.50±18.89 vs. 337.70±11.90, P < 0.01), and FIB was slightly lower than that in the non-critically ill group (g/L: 3.28±0.19 vs. 3.67±0.14, P > 0.05). Correlation analysis showed that pSIC score was significantly positively correlated with MPV/PLT ratio and coagulation indicators including PT, APTT and INR in pediatric sepsis (r value was 0.583, 0.571, 0.296 and 0.518, respectively, all P < 0.01), and MPV/PLT ratio was also significantly positively correlated with PT, APTT and INR (r value was 0.300, 0.203 and 0.307, respectively, all P < 0.05). Multivariate Logistic regression analysis showed that pSIC score and MPV/PLT ratio were independent risk factors for pediatric sepsis and critical pediatric sepsis [pediatric sepsis: odds ratio (OR) and 95% confidence interval (95%CI) for pSIC score was 14.117 (4.190-47.555), and the OR value and 95%CI for MPV/PLT ratio was 1.128 (1.059-1.202), both P < 0.01; critical pediatric sepsis: the OR value and 95%CI for pSIC score was 8.142 (3.672-18.050), and the OR value and 95%CI for MPV/PLT ratio was 1.068 (1.028-1.109), all P < 0.01]. ROC curve analysis showed that pSIC score and MPV/PLT ratio had certain application value in the diagnosis of pediatric sepsis [area under the ROC curve (AUC) and 95%CI was 0.754 (0.700-0.808) and 0.720 (0.643-0.798), respectively] and the determination of critical pediatric sepsis [AUC and 95%CI was 0.849 (0.778-0.919) and 0.731 (0.632-0.830)], and the combined AUC of the two indictors was 0.815 (95%CI was 0.751-0.879) and 0.872 (95%CI was 0.806-0.938), respectively. CONCLUSIONS pSIC score and MPV/PLT ratio have potential application value in the diagnosis of pediatric sepsis and the determination of critical pediatric sepsis, and the combined application of both is more valuable.
Humans ; Sepsis/complications* ; Platelet Count ; Mean Platelet Volume ; Retrospective Studies ; Child ; Blood Coagulation Disorders/diagnosis* ; Intensive Care Units, Pediatric ; Male ; Female ; Partial Thromboplastin Time ; Child, Preschool ; Blood Coagulation ; International Normalized Ratio ; Infant

Objective:This study aimed at investigating the efficacy and safety of eltrombopag in the treatment of adult primary immune thrombocytopenia (ITP) and evaluated the factors influencing its efficacy and side effects.Methods:A total of 198 patients with adult ITP who were admitted to Tianjin Medical University General Hospital between January 2018 and March 2022 were retrospectively analyzed. The efficacy of each starting dose of eltrombopag was evaluated, and adverse events were analyzed. The factors influencing efficacy were investigated, including sex, age, adult ITP type, platelet antibodies, and combined drug treatments.Results:Of the 198 patients, 70 males and 128 females with a median age of 45 years (18-88 years) were included; 130 (65.7%) had newly diagnosed adult ITP, 25 (12.6%) had persistent adult ITP, and 43 (21.7%) had chronic adult ITP. The bleeding event scores at baseline were assessed; 84.3% had scores of<4 and 15.7% had scores of ≥4. The eltrombopag response rate (initial response) at 6 weeks was 78.8% (complete response [CR]: 49.0%; CR1: 14.6%; CR2: 15.2%). The median response time to eltrombopag was 7 (7, 14) days. The initial response rates to 25, 50, and 75 mg eltrombopag were 74.1%, 85.9%, and 60.0%, respectively ( P=0.031). The initial response rate to the 50 mg dose was significantly higher than that of the 25-mg and 75-mg doses. Two patients received 100 mg as the starting dose, and their initial response was 0. Regarding dose adjustment, 70.7% of the patients remained on the starting dose, 8.6% underwent dose adjustment to 50 mg, and 6.1% underwent dose adjustment to 75 mg. Another two patients underwent dose adjustment to 100 mg. After dose adjustment, the persistent response rates were 83.6%, 85.3%, and 85.7% for the 25-, 50-, and 75-mg doses, respectively, with no significant difference. After dose adjustment, the sustained efficacy rate for the 100-mg dose (4 patients) was 100.0%. After 6 weeks of treatment with eltrombopag, the overall bleeding score of patients with ITP decreased. The number of patients with a score of ≥4 decreased to 0, the number of patients with a score of<4 decreased, and there was no significant change in the number of patients with a score of 1-2. The most common adverse event associated with eltrombopag was impaired liver function (7.7%). No thrombosis events or other adverse events were observed. ITP type and number of megakaryocytes significantly affected the initial response to eltrombopag. The initial response rates to eltrombopag for newly diagnosed adult ITP, persistent adult ITP, and chronic adult ITP were 85.3%, 56.0%, and 76.2%, respectively ( P=0.003). For megakaryocytes, the initial response rates were 61.8%, 87.1%, and 84.3% ( P=0.009) for the decreased, normal, and increased megakaryocyte groups, respectively. Conclusion:Eltrombopag, as a second-line or higher treatment for adult ITP, has a rapid onset of action and good safety. The initial response rate is significantly higher with a dose of 50 mg than with a dose of 25 mg. Patients with newly diagnosed ITP and those with normal or increased megakaryocyte numbers have a higher initial response rate to eltrombopag.

Objective:To explore the mechanism of Eucommiae Cortex- Epimedii Folium herbal pair in the treatment of osteoporosis through network pharmacology, molecular docking, and molecular dynamics methods. Methods:Search the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and relevant literature to screen the active compounds of Eucommiae Cortex- Epimedii Folium herbal pair. Using TargetNet, SwissTargetPrediction, and STITCH databases to predict the target of active compounds. GeneCards, OMIM, TTD and DisGeNET databases were used to screen the related targets of osteoporosis, and the intersection targets were obtained by Venny 2.1.0 online tool. Using STRING database for protein-protein interaction (PPI) network analysis. Construct a network diagram using Cytoscape 3.8.2 software and perform network feature analysis to determine key targets and core compounds. Using R 3.6.3 software for gene ontology (GO) functional annotation and Kyoto Encyclopedia of genes and genomes (KEGG) signaling pathway analysis. Apply SYBYL-X 2.1.1 software to perform molecular docking between core compounds and key targets, and use GROMACS 2021.6 software for molecular dynamics simulation. Results:Totally 47 active compounds, 329 targets related to compounds, 4 604 targets related to osteoporosis, and 210 intersecting targets of Eucommiae Cortex- Epimedii Folium herbal pair were selected. Network feature analysis showed that luteolin, quercetin, kaempferol, caffeic acid, chryseriol, and pinoresinol were core compounds, while protein kinase B1(Akt1), interleukin-6 (IL-6), steroid receptor coactivator (Src), cysteinyl aspartate specific proteinase-3 (CASP3), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), prostaglandin-endoperoxide synthase 2 (PTGS2), mitogen-activated protein kinase 8 (MAPK8), and JUN were key targets. GO analysis showed that biological process (BP) mainly involve cellular hormone metabolism, intracellular receptor signaling pathways, oxidative stress responses, hormone metabolism processes, etc. Cell component (CC) mainly involved membrane rafts, membrane microregions, membrane regions, transcription factor complexes, etc. Molecular function (MF) mainly involved nuclear receptor activity, transcription factor activity, steroid hormone receptors, hormone binding, etc. KEGG analysis showed that the signaling pathways of Eucommiae Cortex- Epimedii Folium herbal pair in the treatment of osteoporosis mainly included osteoclast differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking showed that the core compounds could accurately bind to the active sites of key target proteins, and molecular dynamics analysis further verified the binding stability between the core compounds and key target proteins. Conclusions:The combination of Eucommiae Cortex- Epimedii Folium herbal pair has the characteristics of multiple components, targets, and pathways in the treatment of osteoporosis, laying a theoretical foundation for its clinical use.

YABBY proteins are important transcription factors that regulate morphogenesis and organ development in plants. In order to study the YABBY of strawberry, bioinformatic technique were used to identify the YABBY gene families in Fragaria vesca (diploid) and Fragaria×ananassa (octoploid), and then analyze the sequence characters, phylogeny and collinearity of the family members. The RNA-seq data and the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) technique were used to assay the expression patterns of the family members. A green fluorescent protein (GFP) was fused with FvYABBYs and transiently expressed in tobacco leaf cells for the subcellular localization. As the results, six FvYABBY genes and 26 FxaYABBY genes were identified from F. vesca and F.×ananassa, respectively. The FvYABBY genes were grouped into five clades, and five family members were orthologous with AtYABBY genes of Arabidopsis. In F. vesca, all of the FvYABBYs were basically not expressed not expressed in root and receptacle, while FvYABBY1, FvYABBY2, FvYABBY5 and FvYABBY6 were highly expressed in leaf, shoot, flower and achene. In F.×ananassa, FxaYABBY1, FxaYABBY2, FxaYABBY5 and FxaYABBY6 were expressed in achene, and all FxaYABBY were poorly or not expressed in receptacle. Additionally, under the abiotic stresses of low temperature, high salt and drought, the expression of FvYABBY1, FvYABBY3, FvYABBY4 and FvYABBY6 were down-regulated, FvYABBY5 was up-regulated, and FvYABBY2 was up-regulated and then down-regulated. In tobacco leaf cells, the subcellular localization of FvYABBY proteins were in the nucleus. These results provides a foundation for the functional researches of YABBY gene in strawberry.
Fragaria/genetics* ; Arabidopsis ; Biological Assay ; Cold Temperature ; Computational Biology

Objective:To investigate the relationship between serum estradiol(E2)levels on the day before transcervical resection of adhesion(TCRA)and pregnancy outcomes in moderate-severe intrauterine adhesion(IUA).Methods:Clinical data of patients with moderate-severe IUA diagnosed and received TCRA in the Second Affiliated Hospital of Air Force Medical University from January 2018 to December 2019 were extracted and ana-lyzed.The primary outcome indicator was the pregnancy rate during the 12-month follow-up period.Multiple re-gression analysis,smoothed curve fitting and recursive algorithm analysis were applied in this study.Results:A-mong the 288 patients who met the inclusion criteria,222 met the criteria and were finally included in the analysis.The results of multiple regression analysis showed that the E 2 level on the day before surgery was negatively cor-related with the pregnancy rate after TCRA(aOR 0.77,95% CI 0.63-0.93,P=0.0074).Recursive algorithm a-nalysis showed that when the preoperative serum E2 level was less than 380.6 pmol/L,for every increase of 36.7 pmol/L pregnancy rate decreased by approximately 20% (aOR 0.78,95% CI 0.67-0.89,P=0.0004).Conclusions:The results suggest that preoperative serum E2 levels are negatively associated with pregnancy outcomes in patients with moderate-to-severe IUA.

Objective:To investigate the relationship between serum estradiol(E2)levels on the day before transcervical resection of adhesion(TCRA)and pregnancy outcomes in moderate-severe intrauterine adhesion(IUA).Methods:Clinical data of patients with moderate-severe IUA diagnosed and received TCRA in the Second Affiliated Hospital of Air Force Medical University from January 2018 to December 2019 were extracted and ana-lyzed.The primary outcome indicator was the pregnancy rate during the 12-month follow-up period.Multiple re-gression analysis,smoothed curve fitting and recursive algorithm analysis were applied in this study.Results:A-mong the 288 patients who met the inclusion criteria,222 met the criteria and were finally included in the analysis.The results of multiple regression analysis showed that the E 2 level on the day before surgery was negatively cor-related with the pregnancy rate after TCRA(aOR 0.77,95% CI 0.63-0.93,P=0.0074).Recursive algorithm a-nalysis showed that when the preoperative serum E2 level was less than 380.6 pmol/L,for every increase of 36.7 pmol/L pregnancy rate decreased by approximately 20% (aOR 0.78,95% CI 0.67-0.89,P=0.0004).Conclusions:The results suggest that preoperative serum E2 levels are negatively associated with pregnancy outcomes in patients with moderate-to-severe IUA.

Objective:To investigate the relationship between serum estradiol(E2)levels on the day before transcervical resection of adhesion(TCRA)and pregnancy outcomes in moderate-severe intrauterine adhesion(IUA).Methods:Clinical data of patients with moderate-severe IUA diagnosed and received TCRA in the Second Affiliated Hospital of Air Force Medical University from January 2018 to December 2019 were extracted and ana-lyzed.The primary outcome indicator was the pregnancy rate during the 12-month follow-up period.Multiple re-gression analysis,smoothed curve fitting and recursive algorithm analysis were applied in this study.Results:A-mong the 288 patients who met the inclusion criteria,222 met the criteria and were finally included in the analysis.The results of multiple regression analysis showed that the E 2 level on the day before surgery was negatively cor-related with the pregnancy rate after TCRA(aOR 0.77,95% CI 0.63-0.93,P=0.0074).Recursive algorithm a-nalysis showed that when the preoperative serum E2 level was less than 380.6 pmol/L,for every increase of 36.7 pmol/L pregnancy rate decreased by approximately 20% (aOR 0.78,95% CI 0.67-0.89,P=0.0004).Conclusions:The results suggest that preoperative serum E2 levels are negatively associated with pregnancy outcomes in patients with moderate-to-severe IUA.

Objective:To investigate the relationship between serum estradiol(E2)levels on the day before transcervical resection of adhesion(TCRA)and pregnancy outcomes in moderate-severe intrauterine adhesion(IUA).Methods:Clinical data of patients with moderate-severe IUA diagnosed and received TCRA in the Second Affiliated Hospital of Air Force Medical University from January 2018 to December 2019 were extracted and ana-lyzed.The primary outcome indicator was the pregnancy rate during the 12-month follow-up period.Multiple re-gression analysis,smoothed curve fitting and recursive algorithm analysis were applied in this study.Results:A-mong the 288 patients who met the inclusion criteria,222 met the criteria and were finally included in the analysis.The results of multiple regression analysis showed that the E 2 level on the day before surgery was negatively cor-related with the pregnancy rate after TCRA(aOR 0.77,95% CI 0.63-0.93,P=0.0074).Recursive algorithm a-nalysis showed that when the preoperative serum E2 level was less than 380.6 pmol/L,for every increase of 36.7 pmol/L pregnancy rate decreased by approximately 20% (aOR 0.78,95% CI 0.67-0.89,P=0.0004).Conclusions:The results suggest that preoperative serum E2 levels are negatively associated with pregnancy outcomes in patients with moderate-to-severe IUA.