ObjectiveTo investigate the potential mechanism of heat-sensitive moxibustion on chronic atrophic gastritis （CAG） through the phosphoinositide 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodsFifty-eight SD rats were randomly divided into blank group （n=14） and modeling group （n=44）. Rats in the blank group were fed routinely， while the rats in the modeling group received drinking water containing 1-methyl-3-nitro-1-nitrosoguanidine （MNNG） at a concentration of 140 μg/ml， combined with irregular fasting and feeding for 12 weeks to establish CAG model. After successful modeling， the rats were randomly divided into model group （n=10）， inhibitor group （n=10） and moxibustion group （n=20）. After 40 minutes of suspended moxibustion at "Zhongwan" （CV 12） daily， the rats in the moxibustion group were divided into heat-sensitive moxibustion group （n=10） and non-heat-sensitive moxibustion group （n=9） according to the change of tail temperature during moxibustion. The inhibitor group was bound for 40 minutes daily， and then administered with PI3K/Akt signaling pathway inhibitor， rapamycin solution， by gavage at a dose of 1 mg/kg. The model group received intragastric administration of 1 ml/kg normal saline after 40 minutes of restraint stress each day. All interventions were administered once daily for 28 consecutive days， while the blank group received no intervention. After the intervention finished， the body weight of rats in each group was compared. HE staining was used to observe the histopathological changes of gastric mucosa. The apoptosis-positive rate of gastric mucosal cells was detected by TUNEL assay. Immunohistochemistry was performed to determine the protein levels of matric metalloproteinase-7 （MMP7）， vascular endothelial growth factor A （VEGFA） and epidermal growth factor receptor （EGFR） in gastric mucosa. The mRNA expression levels of PI3K， Akt and mammalian target of rapamycin （mTOR） in gastric mucosal tissues were detected by qPCR. The protein levels of phosphorylated Akt （p-Akt） and phosphorylated mTOR （p-mTOR） in rat gastric mucosal tissues were measured by Western Blotting. ResultsCompared to the blank group， rats in all other groups exhibited decreased body weight， significantly increased gastric mucosal cell apoptosis-positive rates， elevated protein levels of MMP7， VEGFA and EGFR in gastric mucosa， increased mRNA expression levels of PI3K， Akt and mTOR， and enhanced protein expression levels of p-Akt and p-mTOR （P＜0.05 or P＜0.01）. Histopathological examination revealed thinning of the gastric mucosa， glandular disorganization and atrophy， accompanied by intestinal metaplasia.Compared to the model group， the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group all showed significant improvements in the above-mentioned indicators （P＜0.05 or P＜0.01）. Compared to the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group exhibited increased positive rates of gastric mucosal cell apoptosis； the non-heat-sensitive moxibustion group showed increased protein levels of MMP7， VEGFA and EGFR， as well as mRNA expression levels of PI3K， Akt and mTOR， and protein expressions of p-Akt and p-mTOR； the inhibitor group exhibited elevated protein expression level of EGFR （P＜0.05 or P＜0.01）. Histopathological examination showed that the gastric mucosal glands in the heat-sensitive moxibustion group were arranged more regularly， with an approximately normal structural appearance. ConclusionHeat-sensitive moxibustion can improve the body weight of CAG rats and repair gastric mucosal injury. Its therapeutic effects may be mediated by inhibiting excessive activation of gastric mucosal PI3K/Akt signaling pathway， thereby reducing gastric mucosal cell apoptosis.

ObjectiveTo investigate the potential mechanism of heat-sensitive moxibustion on chronic atrophic gastritis （CAG） through the phosphoinositide 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodsFifty-eight SD rats were randomly divided into blank group （n=14） and modeling group （n=44）. Rats in the blank group were fed routinely， while the rats in the modeling group received drinking water containing 1-methyl-3-nitro-1-nitrosoguanidine （MNNG） at a concentration of 140 μg/ml， combined with irregular fasting and feeding for 12 weeks to establish CAG model. After successful modeling， the rats were randomly divided into model group （n=10）， inhibitor group （n=10） and moxibustion group （n=20）. After 40 minutes of suspended moxibustion at "Zhongwan" （CV 12） daily， the rats in the moxibustion group were divided into heat-sensitive moxibustion group （n=10） and non-heat-sensitive moxibustion group （n=9） according to the change of tail temperature during moxibustion. The inhibitor group was bound for 40 minutes daily， and then administered with PI3K/Akt signaling pathway inhibitor， rapamycin solution， by gavage at a dose of 1 mg/kg. The model group received intragastric administration of 1 ml/kg normal saline after 40 minutes of restraint stress each day. All interventions were administered once daily for 28 consecutive days， while the blank group received no intervention. After the intervention finished， the body weight of rats in each group was compared. HE staining was used to observe the histopathological changes of gastric mucosa. The apoptosis-positive rate of gastric mucosal cells was detected by TUNEL assay. Immunohistochemistry was performed to determine the protein levels of matric metalloproteinase-7 （MMP7）， vascular endothelial growth factor A （VEGFA） and epidermal growth factor receptor （EGFR） in gastric mucosa. The mRNA expression levels of PI3K， Akt and mammalian target of rapamycin （mTOR） in gastric mucosal tissues were detected by qPCR. The protein levels of phosphorylated Akt （p-Akt） and phosphorylated mTOR （p-mTOR） in rat gastric mucosal tissues were measured by Western Blotting. ResultsCompared to the blank group， rats in all other groups exhibited decreased body weight， significantly increased gastric mucosal cell apoptosis-positive rates， elevated protein levels of MMP7， VEGFA and EGFR in gastric mucosa， increased mRNA expression levels of PI3K， Akt and mTOR， and enhanced protein expression levels of p-Akt and p-mTOR （P＜0.05 or P＜0.01）. Histopathological examination revealed thinning of the gastric mucosa， glandular disorganization and atrophy， accompanied by intestinal metaplasia.Compared to the model group， the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group all showed significant improvements in the above-mentioned indicators （P＜0.05 or P＜0.01）. Compared to the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group exhibited increased positive rates of gastric mucosal cell apoptosis； the non-heat-sensitive moxibustion group showed increased protein levels of MMP7， VEGFA and EGFR， as well as mRNA expression levels of PI3K， Akt and mTOR， and protein expressions of p-Akt and p-mTOR； the inhibitor group exhibited elevated protein expression level of EGFR （P＜0.05 or P＜0.01）. Histopathological examination showed that the gastric mucosal glands in the heat-sensitive moxibustion group were arranged more regularly， with an approximately normal structural appearance. ConclusionHeat-sensitive moxibustion can improve the body weight of CAG rats and repair gastric mucosal injury. Its therapeutic effects may be mediated by inhibiting excessive activation of gastric mucosal PI3K/Akt signaling pathway， thereby reducing gastric mucosal cell apoptosis.

The introduction of national dementia action plans will further drive the development of service systems for the continuum of care for cognitive disorders. However， current healthcare delivery models are often plagued by resource wastage and inefficiency. Grounded in the medical service chain theory， integrating healthcare and social resources through service teams to build a more efficient service system centered on patients' needs holds promise for improving both the quality and efficiency of care. This article reviews the construction of the continuum of care service chain for cognitive disorders， analyzes the potential value of social prescribing as an innovative service model， and explores the role of digital platforms in optimizing care process coordination and enabling information sharing， with the aim of providing a practical reference for the coordinated operation of the continuum of care for cognitive disorders.

Objective To determine the related substances in esmolol hydrochloride injection by HPLC method. Methods A Waters XBridge TM C₁₈ （4.6 mm×150 mm,5 µm） column packed with octadecylsilane-bonded silica gel was used, with phosphate buffer （3.0 g of potassium dihydrogen phosphate was taken, dissolved in water and diluted to 650 ml）-acetonitrile-methanol （65∶15∶20） as the mobile phase A, and mobile phase A mixed with methanol （65∶35） as the mobile phase B. The related substances in the test sample and those generated after forced degradation were qualitatively and quantitatively analyzed by the impurity reference standard method, with an injection volume of 20 μl, a column temperature of 30℃, a flow rate of 1.0 ml/min and a detection wavelength of 222 nm. Results The separation between esmolol hydrochloride and neighboring impurities as well as between each impurity was greater than 1.5; the impurities showed good linearity in their respective linear ranges （r>0.999）. The average recovery of impurity a （Imp-a） was 99.1% with an RSD of 0.56%; the average recovery of impurity b（Imp-b）was 96.0% with an RSD of 0.98%; the average recovery of impurity c （Imp-c） was 100.7% with an RSD of 1.24%; the average recovery of impurity d （Imp-d） was 99.0% with an RSD of 0.12%; the average recovery of impurity e （Imp-e） was 100.7% with an RSD of 0.64%; and the impurity f （Imp-f） average recovery was 101.7% with an RSD of 3.26%; impurity g （Imp-g） average recovery was 99.1% with an RSD of 1.45%. Conclusion This method could evaluate the quality of esmolol hydrochloride injection more accurately than the current standard and could provide data reference for the quality evaluation system.

Gut microbial communities are likely remodeled in tandem with accumulated physiological decline during aging, yet there is limited understanding of gut microbiome variation in advanced age. Here, we performed a metagenomics-based enterotype analysis in a geographically homogeneous cohort of 367 enrolled Chinese individuals between the ages of 60 and 94 years, with the goal of characterizing the gut microbiome of elderly individuals and identifying factors linked to enterotype variations. In addition to two adult-like enterotypes dominated by Bacteroides (ET-Bacteroides) and Prevotella (ET-Prevotella), we identified a novel enterotype dominated by Escherichia (ET-Escherichia), whose prevalence increased in advanced age. Our data demonstrated that age explained more of the variance in the gut microbiome than previously identified factors such as type 2 diabetes mellitus (T2DM) or diet. We characterized the distinct taxonomic and functional profiles of ET-Escherichia, and found the strongest cohesion and highest robustness of the microbial co-occurrence network in this enterotype, as well as the lowest species diversity. In addition, we carried out a series of correlation analyses and co-abundance network analyses, which showed that several factors were likely linked to the overabundance of Escherichia members, including advanced age, vegetable intake, and fruit intake. Overall, our data revealed an enterotype variation characterized by Escherichia enrichment in the elderly population. Considering the different age distribution of each enterotype, these findings provide new insights into the changes that occur in the gut microbiome with age and highlight the importance of microbiome-based stratification of elderly individuals.
Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Bacteroides ; China ; Diabetes Mellitus, Type 2/microbiology* ; Escherichia coli/classification* ; Gastrointestinal Microbiome/genetics* ; Metagenomics ; East Asian People

OBJECTIVE: Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism. METHODS: Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model. RESULTS: PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis. CONCLUSION These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

Objective: To explore the efficacy of focal radiofrequency ablation (RFA) in the treatment of low-to-intermediate risk localized prostate cancer and its impact on postoperative urinary control and sexual function recovery，in order to explore the feasibility of minimally invasive methods for the treatment of localized prostate cancer. Methods: Clinical data of 28 patients with low-to-intermediate risk localized prostate cancer who underwent RFA in Nanjing Drum Tower Hospital，Affiliated Hospital of Medical School during Jun.2017 and Feb.2021 were retrospectively analyzed.The 5-year failure-free survival (FFS) rate，surgery related complications，postoperative urinary control and sexual function were collected.The differences between the survival curves of patients in the low-risk and intermediate-risk subgroups were assessed with log-rank test and Breslow test. Results: All surgeries were successfully completed under local anesthesia.During the median follow-up of 43 (40-49) months，the 5-year FFS rate predicted by Kaplan-Meier method was 78.57%; 25 patients (89.29%) did not experience surgery-related complications; 27 patients (96.43%) were able to control urination; 1 patient developed new-onset sexual dysfunction.There was no significant difference in the survival curves between patients in the low-risk and intermediate-risk groups (P>0.05). Conclusion: RFA for patients with low-to-intermediate risk localized prostate cancer has good clinical efficacy，little impact on urinary control and sexual function recovery，and few postoperative complications，which can be used as one of the treatment options for these patients.

Objective:To establish three machine learning prediction models based on CT imaging characteristics of papillary thyroid carcinoma (PTC) , and use SHAP (shapley additive explanations) analysis to investigate the contribution of each CT image features in the best model.Methods:CT imaging features in 426 cases of 440 PTCs confirmed pathologically from Jan. 2016 to Jan. 2021 at the affiliated Hangzhou First People’s Hospital of Westlake University Medical School were retrospectively analyzed. compared with 467 cases of 528 nodular goiter (NG) , evaluating the distribution of four CT characteristics: cookie bite sign, enhanced range of narrowing/blur (ERNB) , microcalcifications, and irregular shape. We split the data into 8∶2 ratio for training and testing sets, then constructed three machine learning models using XGBoost, RF, and SVM. Based on AUC, accuracy, F1 score, and other metrics, we selected the best model. Lastly, we used SHAP values to assess each CT feature’s contribution and positive/negative effects on the model.Results:Among 440 PTC and 528 NG nodules, CT features like cookie bite sign, ERNB, microcalcifications, and irregular shape occurred in 326 and 30 ( χ 2=483.05, P<0.001) , 363 and 106 ( χ 2=374.45, P<0.001) , 158 and 53 ( χ 2=94.24, P<0.001) , and 354 and 52 ( χ 2=491.34, P<0.001) nodules, respectively. The machine learning models built using XGBoost, RF, and SVM had AUC, accuracy, and F1 scores ranging from 0.884~0.925, 0.867~0.873, and 0.844~0.854 respectively on the training set. On the test set, the scores ranged from 0.869~0.923, 0.845~0.871, and 0.803~0.845. Among them, the XGBoost model demonstrated the highest diagnostic performance on the test set. Among the four CT features, irregular shape had the highest absolute SHAP value, positively contributing to PTC diagnosis. Conclusion:XGBoost model showed the highest PTC diagnostic performance. Irregular shape had the greatest positive impact on PTC diagnosis.

Objective:To investigate the changes of lymphocyte to monocyte ratio (LMR), matrix metalloproteinase-2 (MMP-2), hypoxia inducible factor-1 (HIF-1 α) in patients with breast cancer undergoing surgical resection before and after radiotherapy and their relationship with short-term prognosis.Methods:106 patients with breast cancer who underwent surgical resection and radiotherapy from Jan. 2021 to Jan. 2024 were analyzed as the study subjects. All patients received the same scheme of radiotherapy. The changes of LMR, MMP-2, and HIF-1 α levels at different time points before and after radiotherapy were recorded, and the clinical efficacy of the two groups of patients after radiotherapy was compared. According to the short-term efficacy after radiotherapy, the patients were divided into 31 patients with poor efficacy (progression+deterioration) and 75 patients with good efficacy (complete remission+effective remission+partial remission). The basic clinical data of the two groups were compared. The binary regression analysis was used to analyze the factors that affect the short-term prognosis of patients with breast cancer who had undergone surgery after radiotherapy. A risk prediction model was constructed, and the ROC analysis model was used to predict the value.Result:Compared with before radiotherapy, LMR decreased and MMP-2 and HIF-1 α increased after one week of radiotherapy ( t=2.68, -2.76, -1.96, P=0.008, 0.006, 0.052); After one course of radiotherapy and three courses of radiotherapy, LMR increased and MMP-2 and HIF-1 α decreased ( t=-3.02, 5.14, 5.86, all P<0.05; t=-7.95, 19.80, 21.36, all P<0.001). Low expression of LMR, high expression of MMP-2 and high expression of HIF-1 α are independent risk factors for poor short-term prognosis of breast cancer patients after radiotherapy. LMR、MMP-2、HIF-1α、The prediction model can predict the poor short-term prognosis of breast cancer patients after radiotherapy. The AUC values were 0.780 (95% CI: 0.674~0.887), 0.759 (95% CI: 0.659~0.859), 0.840 (95% CI: 0.748~0.931), and 0.887 (95% CI: 0.808~0.965), respectively. When taking the cut-off values, the sensitivities were 0.853, 0.903, 0.677, and 0.920, and the specificities were 0.677, 0.533, 0.933, and 0.774, respectively. Bootstrap method (B=1000) was used to perform internal validation on the prediction model of poor short-term prognosis of breast cancer patients after radiotherapy. The results showed that the prediction curve after deviation correction was close to the ideal state, and the C-index reached 0.774, indicating that the model had strong prediction ability. In addition, the decision curve of the model shows that the net profit is always positive and better than the two invalid reference lines within the threshold probability range of 0.1 to 1.0. Conclusion:LMR of postoperative radiotherapy patients with breast cancer decreased first and then increased, MMP-2 and HIF-1 α increased first and then decreased, all of which are independent predictors of short-term prognosis. The combined model has a significant predictive effect on poor efficacy and can be used as an important reference for clinical prognosis evaluation.