Objective:To discuss the protective effect of TUG-891 on ischemic stoke(IS)induced by ischemia-hypoxia,and to clarify its potential mechanism.Methods:A total of 60 healthy male C57BL/6 mice were randomly divided into sham operation group(n=20),model group[distal middle cerebral artery occlusion(dMCAO)group,n=20],and model+TUG-891 group(dMCAO+TUG-891 group,n=20).After modeling,the mice were intraperitoneally injected with TUG-891 solution(35 mg·kg?1·d?1)for 3 consecutive days.Modified neurological severity score(mNSS)and rotarod test were used to evaluate the neurological function of the mice in various groups;2,3,5-triphenyltetrazolium chloride(TTC)staining was used to observe the cerebral infarction volumes of the mice in various groups;biochemical method was used to detect the malondialdehyde(MDA)level and superoxide dismutase(SOD)activity in the supernatant of brain tissue of the mice in various groups;Hematoxylin-Eosin(HE)and NISSL staining were used to observe the pathomerphology of brain tissue of the mice in various groups;terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining was used to detect the apoptotic indexes of neuronal cells in brain tissue of the mice in various groups;Western blotting method was used to detect the expression levels of glucose-regulated protein 78(GRP78),protein kinase R-like endoplasmic reticulum kinase(PERK),phosphorylated PERK(p-PERK),and C/EBP homologous protein(CHOP)proteins in brain tissue of the mice in various groups.Results:The mNSS and rotarod test results shoued that compared with sham operation group,the mNSS of the mice in dMCAO group was significantly increased(P<0.01),and the time on the rod was significantly decreased(P<0.01);compared with dMCAO group,the mNSS of the mice in dMCAO+TUG-891 group was decreased(P<0.05),and the time on the rod was increased(P<0.05).The TTC staining results shoued that compared with sham operation group,the volume of white infarct foci in the cerebral cortex of the mice in dMCAO group was increased(P<0.01);compared with dMCAO group,the cerebral infarction volume of the mice in dMCAO+TUG-891 group was significantly decreased(P<0.01).The HE staining results showed that compared with sham operation group,the cortex of the mice in dMCAO group was severely damaged,manifested by disordered arrangement of neuronal cells and obvious nuclear pyknosis in the infarct area,and the morphology of cortical infarct area of the mice in dMCAO+TUG-891 group was improved;the NISSL staining results showed that the Nissl bodies in the cortical infarct area of the mice in dMCAO group became thinner,elongated,and lost more.The pathological damage of brain tissue of the mice in dMCAO+TUG-891 group was significantly improved.Compared with sham operation group,the MDA level in brain tissue of the mice in model group was significantly increased(P<0.01),and the SOD activity was decreased(P<0.01);compared with model group,the MDA level in brain tissue of the mice in TUG-891 group was significantly decreased(P<0.01),and the SOD activity was significantly increased(P<0.01).The TUNEL staining results showed that compared with sham operation group,the apoptotic index of neuronal cells in brain tissue of the mice in dMCAO group was increased(P<0.01);compared with dMCAO group,the apoptotic index of neuronal cells in brain tissue of the mice in dMCAO+TUG-891 group was decreased(P<0.01).Compared with sham operation group,the expression levels of GRP78,p-PERK,and CHOP proteins in brain tissue of the mice in dMCAO group were increased(P<0.05);compared with dMCAO group,the expression levels of GRP78,p-PERK,and CHOP proteins in brain tissue of the mice in dMCAO+TUG-891 group were decreased(P<0.05).Conclusion:TUG-891 can alleviate neurological injury caused by ischemic stroke,and its mechanism may be related to the inhibition of endoplasmic reticulum stress and apoptosis.

Objective:To evaluate the value of a combined model based on primary lesion 18F-fluorodeoxyglucose ( 18F-FDG) PET/CT radiomics for predicting lymph node metastasis in non-small cell lung cancer (NSCLC) . Methods:A retrospective analysis was conducted on the clinical data of 203 NSCLC patients who underwent pre-treatment PET/CT imaging at Nanjing Drum Tower Hospital from June 2013 to July 2023. Patients were randomly assigned to the training set ( n=142) and the validation set ( n=61) at a ratio of 7∶3. A predictive model was developed in the training set, and its predictive performance and clinical application value were assessed in both the training and validation sets. Traditional PET/CT parameters and PET/CT radiomics features of the primary lesion were obtained by 3D-slicer software. Least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting were performed to extract features. Support vector machine was used to construct a radiomics score (Radscore). Univariate and multivariate logistic regression analysis was used to predict the influencing factors of lymph node metastasis in NSCLC patients and to establish models. Predictive performance of the models was evaluated by receiver operator characteristic (ROC) curves and clinical application value was assessed by calibration curves and decision curve analysis (DCA) . Results:Among 203 NSCLC patients, 116 had lymph node metastasis, with 64 cases in the training set and 52 cases in the validation set. Three complementary classical machine learning methods were used for feature screening, and finally 10 radiomics features were obtained. The optimal threshold for Radscore-PET was 0.43 and the optimal threshold for Radscore-CT was 0.39. Univariate analysis showed that, sex ( OR=0.48, 95% CI: 0.24-0.95, P=0.036), tumor marker levels ( OR=3.81, 95% CI: 1.84-7.91, P<0.001), long diameter of tumor ( OR=2.56, 95% CI: 1.27-5.16, P=0.009), short diameter of tumor ( OR=3.73, 95% CI: 1.75-7.92, P=0.001), vacuolar sign ( OR=0.32, 95% CI: 0.12-0.86, P=0.024), ring-like metabolism ( OR=3.67, 95% CI: 1.33-10.13, P=0.012), maximum standardized uptake value (SUV max) ( OR=6.57, 95% CI: 3.03-14.25, P<0.001), metabolic tumor volume (MTV) ( OR=2.91, 95% CI: 1.43-5.92, P=0.003), total lesion glycolysis (TLG) ( OR=4.23, 95% CI: 2.08-8.59, P<0.001), Radscore-PET ( OR=21.93, 95% CI: 9.04-53.20, P<0.001) and Radscore-CT ( OR=13.72, 95% CI: 6.12-30.76, P<0.001) were all influencing factors for predicting lymph node metastasis in NSCLC patients. Multivariate analysis showed that, tumor marker levels ( OR=2.55, 95% CI: 1.11-5.90, P=0.028), vacuolar sign ( OR=0.26, 95% CI: 0.08-0.83, P=0.023), SUV max ( OR=5.94, 95% CI: 1.99-17.75, P=0.001), Radscore-PET ( OR=25.51, 95% CI: 5.92-110.22, P<0.001), and Radscore-CT ( OR=8.68, 95% CI: 2.73-27.61, P<0.001) were independent influencing factors for predicting lymph node metastasis in patients with NSCLC. Based on the above independent influencing factors, models were constructed: the traditional model (tumor marker levels, vacuolar sign, SUV max), the PET model (SUV max, Radscore-PET), the CT model (vacuolar sign, Radscore-CT), and the combined model (tumor marker levels, vacuolar sign, SUV max, Radscore-PET, Radscore-CT). ROC curve analysis showed that, the area under curve (AUC) of the traditional, PET, CT, and combined models in the training set were 0.75 (95% CI: 0.67-0.82), 0.90 (95% CI: 0.84-0.95), 0.85 (95% CI: 0.78-0.90), and 0.94 (95% CI: 0.88-0.97), respectively. The predictive value of the combined model was higher than that of the traditional model ( Z=5.01, P<0.001), the PET model ( Z=1.99, P=0.047), and the CT model ( Z=3.25, P=0.001). In the validation set, the AUCs for the traditional model, PET model, CT model, and combined model were 0.65 (95% CI: 0.52-0.77), 0.86 (95% CI: 0.74-0.93), 0.85 (95% CI: 0.73-0.93), and 0.90 (95% CI: 0.80-0.96), respectively. The predictive value of the combined model was superior to that of the traditional model ( Z=3.23, P=0.001). The sensitivity and specificity of the combined model in the training set were 84.37% and 91.03%, while in the validation set, the sensitivity and specificity were 82.61% and 94.74%, respectively. Calibration curves showed a good agreement between the predicted and actual probabilities in both the training and validation sets. DCA showed that the combined models had good discriminative ability in both the training and validation sets. Conclusions:Tumor marker levels, vacuolar sign, SUV max, Radscore-PET, and Radscore-CT are all independent influencing factors for predicting lymph node metastasis in patients with NSCLC. The combined model based on these factors demonstrates excellent predictive performance and clinical application value for predicting lymph node metastasis in NSCLC.

The tumor microenvironment (TME) is the cellular milieu in which tumor cells thrive, comprising interacting cells and associated factors that form a complex network of interactions, directly or indirectly influencing the initiation, progression, and metastasis of lung cancer. Through TCM pattern identification, it has been observed thatphlegm-pathogen is closely associated with disorder in the inflammatory-metabolic-immune microenvironments of lung cancer. This involves three key pathological mechanisms: "phlegm-stasis complicated by toxin, qi deficiency with exuberant phlegm, and phlegm-pathogen impairing healthy qi". Molecular mechanism studies have revealed that phlegm-resolving agents can extensively modulate multiple targets or pathways, thereby remodeling the inflammatory-metabolic-immune microenvironments of lung cancer. Consequently, a comprehensive therapeutic strategy integrating "resolving phlegm, dispelling stasis, and detoxifying; supplementing qi, warming yang, and resolving phlegm; and reinforcing healthy qi, tonifying the lung, and eliminating phlegm" is essential to reshape the lung cancer TME and enhance antitumor efficacy.

ObjectiveTo investigate the ameliorative effect and mechanism of total saponins of Codonopsis Radix （TSC） on learning and memory impairment induced by D-galactose in aging mice. MethodTwenty-four male C57BL/6J mice were randomly assigned into four groups （n=6）： normal group， model group （200 mg·kg^-1 D-galactose）， TSC group （200 mg·kg^-1）， and donepezil group （3 mg·kg^-1）. After one week of pre-treatment， the mice in the model， TSC， and donepezil groups were administrated with corresponding agents for 8 weeks. In the ninth week， the Morris water maze test was performed to assess the learning and memory abilities. Histopathological changes in the brain were evaluated by hematoxylin-eosin （HE） and Nissl staining. Immunohistochemistry was used to detect the expression of nuclear factor kappa-B （NF-κB）， tumor necrosis factor-α （TNF-α）， and brain-derived neurotrophic factor （BDNF） in the brain tissue. The serum levels of glutathione peroxidase （GSH-Px）， catalase （CAT）， superoxide dismutase （SOD）， malondialdehyde （MDA）， TNF-α， interleukin-1β （IL-1β）， and interleukin-18 （IL-18） were measured by enzyme-linked immunosorbent assay， on the basis of which the effects of TSC on neuroinflammation and memory impairment in D-galactose-induced aging mice were assessed. ResultCompared with the normal group， the model group exhibited decreased cognitive function， decreased activities of CAT， SOD， and GSH-Px in the serum （P<0.01）， and upregulated levels of MDA， TNF-α， IL-1β， and IL-18 （P<0.01）. In addition， partial neuronal damage and degeneration were observed in the hippocampus and cortex of the model group， accompanied by downregulated BDNF expression （P<0.05） and upregulated NF-κB and TNF-α expression （P<0.05）. Compared with the model group， TSC alleviated D-galactose-induced cognitive dysfunction， enhanced the activities of CAT， SOD， and GSH-Px （P<0.01）， lowered MDA， TNF-α， IL-1β， and IL-18 levels （P<0.01）， and ameliorated the pathological changes in the hippocampus and cerebral cortex. Additionally， TSC upregulated BDNF expression （P<0.05， P<0.01） and downregulated NF-κB and TNF-α expression （P<0.05， P<0.01） in the hippocampus and cerebral cortex. ConclusionTSC exerts a protective effect on cognitive dysfunction induced by D-galactose in aging mice by inhibiting oxidative stress and inflammation.

Objective:To investigate the therapeutic effect of high-flow nasal cannula oxygen therapy (HFNC) and non-invasive positive pressure ventilation (NPPV) on patients with pulmonary edema caused by seawater drowning.Methods:A retrospective analysis method was used. Based on the Utstein database of emergency drowning in the First Hospital of Qinhuangdao, the clinical data of patients with seawater drowning pulmonary edema admitted to the emergency medicine department of the First Hospital of Qinhuangdao from January 1, 2019 to December 31, 2022 were collected. The patients were divided into NPPV group and HFNC group according to different ventilation methods. The general data, endotracheal intubation rate in 7 days, arterial blood gas analysis indexes [arterial partial pressure of oxygen (PaO 2), arterial partial pressure of carbon dioxide (PaCO 2), arterial oxygen saturation (SaO 2)] and hemodynamic indexes (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, blood lactic acid) before and after treatment, length of stay in intensive care unit (ICU), oxygen therapy comfort of the two groups were compared. Results:A total of 54 patients were enrolled, including 21 patients in the NPPV group and 33 patients in the HFNC group. There were no significant differences in gender, age, state of consciousness and other general information between the two groups. Compared with NPPV group, the rate of endotracheal intubation in HFNC group within 7 days was significantly lower [24.2% (8/33) vs. 33.3% (7/21), P < 0.05]. Before treatment, there were no significant differences in arterial blood gas analysis and hemodynamics between the two groups. After treatment, the above indexes in both groups were significantly improved compared with those before treatment, and PaO 2, SaO 2, systolic blood pressure, diastolic blood pressure and mean arterial pressure in HFNC group were significantly higher than those in NPPV group [PaO 2 (mmHg, 1 mmHg≈0.133kPa): 93.56±6.37 vs. 82.14±6.25, SaO 2: 1.02±0.09 vs. 0.95±0.11, systolic blood pressure (mmHg): 117.37±8.43 vs. 110.42±8.38, diastolic blood pressure (mmHg): 79.43±7.61 vs. 72.21±4.32, mean arterial pressure (mmHg): 92.34±6.32 vs. 85.12±5.38], PaCO 2, heart rate and blood lactic acid were significantly lower than those in NPPV group [PaCO 2 (mmHg) : 34.26±5.63 vs. 37.24±6.22, heart rate (times/min): 73.38±7.56 vs. 86.25±5.41, blood lactic acid (mmol/L): 1.38±0.36 vs. 2.25±1.14], and the differences were statistically significant (all P < 0.05). In addition, the length of ICU stay in HFNC group was significantly shorter than that in NPPV group (days: 13.30±2.38 vs. 16.27±4.26), and the comfort rate of oxygen therapy was significantly higher than that in NPPV group [66.7% (22/33) vs. 42.8% (9/21)], with statistical significance (all P < 0.05). Conclusion:HFNC can improve the oxygenation of patients with pulmonary edema caused by seawater drowning, improve hemodynamics, reduce the rate of tracheal intubation, shorten the length of ICU stay, and improve the comfort of oxygen therapy, which has certain clinical application value.

Chronic myeloid leukemia (CML) with e6a2 transcript type is very rare in clinic,which is usually related to disease aggressiveness. Its clinical characteristics and relationship with tyrosine kinase inhibitor efficacy are still unclear. In this paper, the clinical characteristics and related laboratory tests of a patient with e6a2 fusion gene positive CML characterized by multiple osteolytic bone destruction throughout the body and eosinophil infiltration in gastrointestinal tract, lymph nodes and other organs were retrospectively analyzed, and the relevant literature was reviewed. The patient was Ph chromosome positive with chromosome +8, and the common BCR::ABL1 transcript of CML was negative, but e6a2 transcript was positive detected by RT-PCR. The patient was treated with dasatinib 100 mg/d. Three months later, the patients achieved CHR, CCyR and MR4.0. However, the e6a2 transcript is very rare in clinical practice, and more cases of e6a2 transcript need to be studied to clarify its clinical characteristics and improve the treatment effect of these rare cases.

Objective To explore the medication law of Professor Wang Qingguo for the treatment of insomnia based on data mining technology.Methods Paper-based prescriptions for Professor Wang Qingguo's treatment of insomnia from December 2016 to August 2023 were collected and a database was constructed.The screened prescriptions were subjected to data mining such as frequency statistics,association rule analysis,and clustering analysis.Results Totally 399 effective outpatient prescriptions were screened-out,involving 276 kinds of Chinese materia medica,with a total frequency of 6738 times.There were 38 Chinese materia medica with a frequency of use≥50.The properties were mainly warm,cold and mild,the tastes were mainly sweet,bitter and pungent,and mainly belong to the lung,spleen and heart meridians.Association rule analysis showed that the most commonly used drug combinations were"Fructus Tritici Levis-Scutellariae Radix-Bupleuri Radix","Pericarpium Citri Reticulatae-Scutellariae Radix-Pinelliae Rhizoma",etc.Association rule network analysis obtained a core prescription containing 12 kinds of Chinese materia medica for insomnia.Four new drug combinations were obtained by clustering analysis.Conclusion Professor Wang's treatment of insomnia has the characteristics of following the original meaning of Huang Di Nei Jing and Nan Jing,making good use of the classical prescription,applying combined prescription,flexible use of prescription,combining ancient and modern prescriptions,using specific medicine.It deeply reflects the academic view of"Tongping Zhihe".

Codonopsis Radix is a Codonopsis plant belonging to Campanulaceae family.It is widely used as a Chinese medicinal for invigorating qi in Chinese medicine clinics.The chemical compositions of Codonopsis Radix mainly contain flavonoids,alkaloids,sugars,saponins,steroids,amino acids,etc..It mainly exhibits the pharmacological effects such as enhancing the immune system function,improving gastrointestinal function,anti-inflammation,anti-tumor,improving the ability of learning and memory,regulating the cardio-cerebral vascular system,and slowing down the aging process,and so on.Based on a large number of literature studies on Codonopsis Radix at home and abroad in recent years,this paper summarizes its pharmacological effects.The aim of the review is to provide a certain theoretical basis and rationale for the research and application of Codonopsis Radix.

Objective:To prepare a 177Lu labeled human epidermal growth factor receptor 2 (HER2) affibody 177Lu-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-maleimide (Mal)-cysteine (Cys)-ZHER 2: 342 ( 177Lu-NOTA-MZHER2 for short), and investigate its labeling process and anti-tumor properties. Methods:Two kinds of buffer systems (sodium acetate buffer system and sodium ascorbate buffer system) were investigated. The effects of pH value, precursor mass and reaction temperature on 177Lu labeling NOTA-MZHER2 were compared to obtain optimal labeling conditions. The radiochemical purity of labeled product was determined by instant thin-layer chromatography (ITLC), and its stabilities in PBS and plasma were observed. Human ovarian cancer cell line SKOV-3 was selected for cell internalization and cytotoxicity test to evaluate cell uptake and killing effect of 177Lu-NOTA-MZHER2. SKOV-3 tumor-bearing mice( n=3) were injected with 177Lu-NOTA-MZHER2, and microSPECT/CT imaging was performed. Another 40 tumor-bearing mice were divided into 22.2 MBq group (tail vein injection with probe of 22.2 MBq), control group (tail vein injection with PBS), low-dose group (tumor injection with probe of 3.7 MBq) and high-dose group (tumor injection with probe of 7.4 MBq). Tumor volume and mass of tumor-bearing mice were monitored after injection, and the anti-tumor effect and toxicity of probe were evaluated. Repeated measurement analysis of variance (Bonferroni method) was used to analyze the data. Results:The optimal labeling condition was 70-80 ℃ for 30 min in the system of sodium acetate buffer solution with pH=4 and precursor mass of 50 μg. Under these conditions, the labeling rate of 177Lu-NOTA-MZHER2 was (99.3±0.4)% and radiochemical purity was >99%. After 12 d in PBS and plasma, the radiochemical purities were (95.0±1.5)% and (95.0±2.1)%. Results of cell experiment showed that the internalization of 177Lu-NOTA-MZHER2 accounted for (29.02±3.50)% of the total uptake, and the survival rate of SKOV-3 cells was (48±6)% with the probe concerntration of 6×10 -3 Bq/L. SPECT imaging showed that 177Lu-NOTA-MZHER2 was still concentrated at the tumor site 96 h after injection with a dose of 18.5 MBq. Relative tumor volume (RTV) of tumor-bearing mice in 22.2 MBq group, high-dose group and low-dose group was significantly different from that in control group ( F=21.75, P<0.001). Twenty days after injection, RTV and relative body mass of the tumor-bearing mice in high-dose group were (140±7)% and (80±9)%, respectively. Compared with control group, high-dose group had obvious anti-tumor effect (both P<0.001). Conclusion:177Lu-NOTA-MZHER2 is successfully prepared, which is simple and efficient, and the probe has good anti-tumor effect.

Objective:To radiolabel hyperbranched polymer (HG)-modified liquid metal nanodroplet (LMND)@HG with 177Lu, and explore the radiotherapy sensitization effect on anti-breast cancer therapy. Methods:The ultrasonication method was used to prepare LMND@HG, and then 177LuCl 3 was mixed with LMND@HG to label 177Lu by alloying reactions. The labeling rate, plasma stability and cytotoxicity of 177Lu-LMND@HG were detected. Xenograft mouse model of breast cancer was constructed, and the tumor inhibition test was performed by an intratumoral injection. The tumor progression was monitored by in vivo imaging system. The mechanism of tumor inhibition was verified by immunohistochemistry and immunofluorescence assays. One-way analysis of variance, repeated measures analysis of variance, and the least significant difference t test were used to analyze the data. Results:177Lu was successfully labeled to LMND@HG with a high labeling efficiency >95%. The product did not require further purification and the plasma radiochemical purity was still higher than 95% after 5 d. The cytotoxicity test showed that a dose of 888 kBq (40 mg/L) 177Lu-LMND@HG had obvious toxicity to 4T1 cells, which was significantly lower than 177LuCl 3 (cell viabilities: (16.48±7.81)% vs (85.77±8.87)%; F=77.81, t=11.73, P<0.001) and LMND@HG ((46.53±5.75)%; t=6.20, P<0.001). The biological distribution results showed that 177Lu-LMND@HG was mainly distributed in tumor tissue 5 d after intratumoral injection. The results of the tumor inhibition experiment showed that 1.48 MBq 177Lu-LMND@HG could significantly inhibit the tumor growth compared with the 177LuCl 3 (tumor volume: (222.66±97.70) vs (789.13±245.04) mm 3;F=18.55, t=4.29, P=0.005). In vivo optical imaging of small animals showed that 1.48 MBq and 3.70 MBq 177Lu-LMND@HG both significantly inhibited the tumor growth. Immunofluorescence and immunohistochemical results showed that 177Lu-LMND@HG caused double-stranded DNA break, and suppressed the tumor growth by inhibiting cell proliferation and angiogenesis. Conclusions:A novel 177Lu-liquid metal-based reactive oxygen species (ROS) radiation sensitizer is successfully prepared in this study. The preparation method is efficient and convenient, and the product has high stability. 177Lu-LMND@HG shows an obvious radiotherapy sensitization effect on breast tumor-bearing mice.