OBJECTIVE To investigate the effect and potential mechanism of toosendanin in enhancing the antileukemic activity of cytosine arabinoside against acute myeloid leukemia （AML） based on the mammalian target of rapamycin complex 1 （mTORC1） signaling pathway.METHODS Female NSG immunodeficient mice were used to establish an AML model via a single γ-ray irradiation followed by a single tail-vein injection of a U937 cell suspension. The effects of cytosine arabinoside （2.5 mg/kg）， toosendanin （1.0 mg/kg）， and cytosine arabinoside+toosendanin （2.5 mg/kg+1.0 mg/kg） on body weight， survival time， peripheral blood routine indicators， histopathological morphology， and the expressions of autophagy-related proteins were explored. Using U937 cells as the subject， the effects of cytosine arabinoside （1 μmol/L）， toosendanin （160 nmol/L）， and cytosine arabinoside+toosendanin （1 μmol/L+160 nmol/L） on the expressions of autophagy-related proteins， mTORC1 signaling pathway-related proteins and mRNAs were investigated. The targeting relationship between toosendanin and the selective autophagy ligand 1 （also known as p62） was validated， and the Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses， as well as molecular docking， were performed. A p62 -knockdown U937 stable cell line was constructed， and the underlying mechanism of toosendanin-induced sensitization was verified.RESULTS Animal experiments confirmed that the combination of toosendanin and cytosine arabinoside significantly improved body weight， survival time and peripheral blood routine indicators in AML mice （ P ＜0.05）， alleviated pathological changes such as leukemic cell infiltration and focal necrosis in bone marrow， liver， and spleen tissues， and modulated the expressions of autophagy-related proteins. Cell experiments confirmed that toosendanin could reverse cytosine arabinoside-induced activation of the autophagy cascade （manifested by downregulation of the protein expressions of microtubule-associated protein 1 light chain 3B and Beclin-1， upregulation the protein expression of p62）， and might inhibit the expression of the downstream Unc-51-like autophagy activating kinase 1 （ULK1） complex （including ULK1， ULK2， autophagy-related protein 13， and FAK family interacting protein of 200 kDa） by activating the mTORC1 signaling pathway （ P ＜0.05）. The sensitizing effect of toosendanin was associated with the inhibition of autophagy and the regulation of the mTORC1 signaling pathway； it could stably bind to p62 via hydrophobic interactions. Mechanism verification experiments indicated that upon p62 knockdown， toosendanin was no longer able to activate the mTORC1 signaling pathway or inhibit autophagy.CONCLUSIONS Toosendanin may enhance chemo-sensitivity of AML cells to cytosine arabinoside by directly targeting the p62 protein， which subsequently activates the mTORC1 signaling pathway， and thereby suppresses cytosine arabinoside-induced protective autophagy.

This article reports the first case of percutaneous closure of patent foramen ovale(PFO)using a biodegradable occluder under echocardiography guidance.The patient is a 43-year-old female diagnosed with PFO-related stroke.The procedure was successfully completed under echocardiography guidance without complications.During the 48-month follow-up period,the patient experienced no recurrent strokes,and the occluder was fully degraded.

Objective To observe the predictability of the corneal stromal reduction with smart pulse technology-as-sisted transperitoneal photorefractive keratomileusis(SPT-TPRK)and femtosecond laser-assisted in situ keratomileusis(FS-LASIK).Methods Patients undergoing laser surgery in the Department of Ophthalmology of the First Affiliated Hos-pital of Xinxiang Medical College from February to September 2023 were selected and divided by surgical modalities into an SPT-TPRK group(21 cases,37 eyes)and an FS-LASIK group(18 cases,32 eyes).The uncorrected visual acuity(UCVA),intraocular pressure,corneal thickness,and corneal epithelial thickness were measured before surgery,1 week,1 month and 3 months after surgery.The cutting deviation was calculated,and the change of corneal stromal thickness was ob-served.The correlation between the predicted corneal stromal reduction and the cutting deviation was analyzed.Results There were significant differences in UCVA among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The UCVA of patients in the FS-LASIK group was significantly higher than that in the SPT-TPRK group 1 week after surgery(P＜0.001).The difference in UCVA was not statistically significant between the two groups 1 month and 3 months after surgery(all P＞0.05).There were significant differences in intraocular pressure among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The FS-LASIK group had a lower intraocular pressure than the SPT-TPRK group 1 week after surgery(P＜0.05),but the difference in intraocular pressure was not statistically significant between the two groups 1 month and 3 months after surgery(all P＞0.05).There was significant difference between predicted cor-neal stromal reductions and actual corneal stromal reductions measured at different time points postoperatively in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The actual corneal stromal reductions were higher than the predicted ones in the SPT-TPRK group at all postoperative time points(all P＜0.05).In the FS-LASIK group,the actual corneal stromal re-ductions were higher than the predicted ones 1 week and 1 month after surgery(all P＜0.05),but the actual and predicted corneal stromal reductions were not significantly different 3 months after surgery(P＞0.05).The cutting deviations were not significantly different between SPT-TPRK and FS-LASIK groups 1 month after surgery(P＞0.05),while the cutting de-viations were significantly different between the two groups 1 week and 3 months after surgery(all P＜0.05).There were significant differences in the change of the stromal thickness among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.05).There was no significant difference in the change of the stromal thickness among different time points in the SPT-TPRK group(all P＞0.05).The stromal thickness showed greater changes 1 month after surgery than that 1 week after surgery in the FS-LASIK group(P＜0.05).There were no significant differences in the change of the stromal thickness between 1 month and 3 months after surgery in the FS-LASIK group(P＞0.05).Correlation analysis showed a positive correlation between the predicted corneal stromal reduction and the cutting deviation in the SPT-TPRK group 1 week after surgery(P＜0.05),but they had no correlation 1 month and 3 months after surgery(all P＞0.05).There was no correlation between the predicted corneal stromal reduction and the cutting deviation in the FS-LASIK group at all post-operative time points(all P＞0.05).Conclusion Patients who receive SPT-TPRK or FS-LASIK can both achieve good visual acuity and a reduction in intraocular pressure.FS-LASIK has better predictability in refractive error correction than SPT-TPRK.

Objective To observe the predictability of the corneal stromal reduction with smart pulse technology-as-sisted transperitoneal photorefractive keratomileusis(SPT-TPRK)and femtosecond laser-assisted in situ keratomileusis(FS-LASIK).Methods Patients undergoing laser surgery in the Department of Ophthalmology of the First Affiliated Hos-pital of Xinxiang Medical College from February to September 2023 were selected and divided by surgical modalities into an SPT-TPRK group(21 cases,37 eyes)and an FS-LASIK group(18 cases,32 eyes).The uncorrected visual acuity(UCVA),intraocular pressure,corneal thickness,and corneal epithelial thickness were measured before surgery,1 week,1 month and 3 months after surgery.The cutting deviation was calculated,and the change of corneal stromal thickness was ob-served.The correlation between the predicted corneal stromal reduction and the cutting deviation was analyzed.Results There were significant differences in UCVA among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The UCVA of patients in the FS-LASIK group was significantly higher than that in the SPT-TPRK group 1 week after surgery(P＜0.001).The difference in UCVA was not statistically significant between the two groups 1 month and 3 months after surgery(all P＞0.05).There were significant differences in intraocular pressure among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The FS-LASIK group had a lower intraocular pressure than the SPT-TPRK group 1 week after surgery(P＜0.05),but the difference in intraocular pressure was not statistically significant between the two groups 1 month and 3 months after surgery(all P＞0.05).There was significant difference between predicted cor-neal stromal reductions and actual corneal stromal reductions measured at different time points postoperatively in both SPT-TPRK and FS-LASIK groups(all P＜0.001).The actual corneal stromal reductions were higher than the predicted ones in the SPT-TPRK group at all postoperative time points(all P＜0.05).In the FS-LASIK group,the actual corneal stromal re-ductions were higher than the predicted ones 1 week and 1 month after surgery(all P＜0.05),but the actual and predicted corneal stromal reductions were not significantly different 3 months after surgery(P＞0.05).The cutting deviations were not significantly different between SPT-TPRK and FS-LASIK groups 1 month after surgery(P＞0.05),while the cutting de-viations were significantly different between the two groups 1 week and 3 months after surgery(all P＜0.05).There were significant differences in the change of the stromal thickness among different time points in both SPT-TPRK and FS-LASIK groups(all P＜0.05).There was no significant difference in the change of the stromal thickness among different time points in the SPT-TPRK group(all P＞0.05).The stromal thickness showed greater changes 1 month after surgery than that 1 week after surgery in the FS-LASIK group(P＜0.05).There were no significant differences in the change of the stromal thickness between 1 month and 3 months after surgery in the FS-LASIK group(P＞0.05).Correlation analysis showed a positive correlation between the predicted corneal stromal reduction and the cutting deviation in the SPT-TPRK group 1 week after surgery(P＜0.05),but they had no correlation 1 month and 3 months after surgery(all P＞0.05).There was no correlation between the predicted corneal stromal reduction and the cutting deviation in the FS-LASIK group at all post-operative time points(all P＞0.05).Conclusion Patients who receive SPT-TPRK or FS-LASIK can both achieve good visual acuity and a reduction in intraocular pressure.FS-LASIK has better predictability in refractive error correction than SPT-TPRK.

Objective·To investigate the efficacy and safety of a dose-reduced,all-oral lenalidomide/melphalan/prednisone acetate(RMP)regimen in elderly and frail patients with newly diagnosed multiple myeloma(NDMM).Methods·Elderly and frail NDMM patients who visited the Department of Hematology of Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,and the Third People's Hospital of Kunshan from April 2018 to March 2024 were retrospectively included.Clinical data and laboratory indicators were collected,and all patients were treated with the RMP regimen.SPSS 27.0 and R software were used for statistical analysis.Independent t-test was applied to normally distributed quantitative data,Mann-Whitney U test to non-normally distributed quantitative data,and x2 test and Fisher's exact probability method to qualitative data.Kaplan-Meier survival curves and Log-rank test were used for survival analysis.Results·Among the 22 elderly and frail NDMM patients treated with RMP,the median age was 76.3(68.4,95.0)years,and the median follow-up time was 25.5 months.The overall response rate(ORR)was 68.2%,and the rate of≥very good partial response(VGPR)was 36.4%.The median progression-free survival(PFS)was 20.53 months.The median PFS in the≤75-year-old group was 25.23(95%CI 12.95?37.52)months,while in the>75-year-old group it was 18.23(95%CI 14.86?21.61)months.There was no significant difference between the two groups.The median PFS in the≥partial response(PR)group was 20.67(95%CI 13.57?27.76)months,and in the

Objective:To investigate the risk of developing pulmonary hypertension (PH) in children with bronchopulmonary dysplasia (BPD) exposed to hemodynamically significant patent ductus arteriosus (hsPDA) and the correlation between PH and exposure to hsPDA.Methods:Retrospective case-control study.The clinical data of extremely premature infants (gestational age <32 weeks) admitted to the Department of Neonatology, Shanghai Children′s Hospital from January 2018 to December 2022 were retrospectively analyzed.All the very premature infants had a corrected gestational age≥36 weeks, required respiratory support, and were diagnosed with BPD.Their echocardiograms were evaluated by a team of physicians specialized in ultrasound.The patients were divided into a non-PH group and a PH group based on whether they were complicated by PH.The risk factors of PH in infant with BPD were analyzed by univariate and multivariate analyses.The influence of hsPDA on the outcome of PH in infant with BPD was analyzed by a Logistic model, whose performance was evaluated by the receiver-operating characteristic (ROC) curve.Results:(1)A total of 147 infants with BPD were included, with 74 cases in the non-PH group and 73 cases in the PH group.There was no significant difference in gestational age[(204.5±11.8) days vs.(201.6±11.5) days] and birth weight[(1 222±273) g vs.(1 153±237) g] between the non-PH and PH groups(all P>0.05).(2)Univariate ANOVA showed the development of PH in children with BPD was significantly related to postnatal positive pressure ventilation resuscitation ( P=0.036), invasive respiratory support ( P=0.002), prenatal glucocorticoids ( P=0.043), intravenous hormones ( P=0.003), liquid restriction ( P<0.001), hypercapnia ( P=0.004), PDA ( P=0.010), and hsPDA ( P<0.001).(3)The Logistic regression analysis suggested that exposure to hsPDA ( OR=5.414, 95% CI: 1.852-15.824, P=0.002) was an independent risk factor for PH development in children with BPD.The ROC curve is plotted through the prediction probability of the model, which has an optimal cut-off value of 42.9% (sensitivity=83.6%, specificity=63.5%, area under the ROC curve=0.794, and Youden index=0.471). Conclusions:Exposure to hsPDA increases the risk and is an independent risk factor of PH development in infants with BPD.

Transcatheter edge-to-edge repair has become the most important and widely recognized method for the treatment of patients with severe mitral regurgitation who are at high risk for surgery.At present,TEER is developing rapidly in China,the operation process tends to be standardized and standardized,and various domestic Clip devices are also constantly developing and improving,but the operation process of this technology is very dependent on the guidance and monitoring of transesophageal echocardiography,and many surgeons often only pay attention to the repair effect of TEER on MR,and ignore the damage of TEE probe to the esophagus.This study reports a case of esophageal erosion occurring in a patient after mitral valve clipping for mitral regurgitation,aiming to enhance awareness among colleagues regarding esophageal injury caused by transesophageal echocardiography probes.

Objective:To investigate the relationship between serum soluble interleukin-2 receptor(sCD25)and insulin-like growth factor-Ⅰ(IGF-Ⅰ)and the immunophenotype and therapeutic efficacy of newly diagnosed multiple myeloma(MM)patients.Methods:125 newly diagnosed MM patients(MM group)who received treatment at Tianmen First People's Hospital from January 2023 to June 2024 were selected,and another 70 healthy individuals who underwent physical examinations at our hospital during the same period were selected(control group).The serum sCD25 and IGF-Ⅰ levels in newly diagnosed MM patients of different stages were compared,and newly diagnosed MM patients were divide into remission group(76 cases)and non remission group(49 cases)based on treatment efficacy,the serum sCD25 and IGF-Ⅰ levels between the remission group and non remission group were compared.The patients were divided into high sCD25 group and low sCD25 group,high IGF-Ⅰ group and low IGF-Ⅰgroup according to the median levels of serum sCD25 and IGF-Ⅰ,the immunophenotypic differences between high sCD25 group and low sCD25 group,as well as high IGF-Ⅰ group and low IGF-Ⅰ group were analyzed.Serum sCD25 and IGF-Ⅰ for evaluating the efficacy of newly diagnosed MM patients were analyzed by receiver operating characteristic(ROC)curve.Factors affecting the therapeutic effect of newly diagnosed MM patients were analyzed by multivariate logistic regression analysis.Results:Serum sCD25 and IGF-Ⅰ levels in the control group were significantly lower than those in the MM group(P＜0.05).There was a statistically significant difference in serum sCD25 and IGF-Ⅰ levels among newly diagnosed MM patients at different stages(P＜0.05).Serum sCD25 and IGF-Ⅰ levels in stage Ⅲ newly diagnosed MM patients were significantly higher than those in stage Ⅰ and Ⅱ(P＜0.05),And stage Ⅱ was higher than that in stage Ⅰ(P＜0.05).The positive expression rate of CD56 in the high sCD25 group was higher than that in the low sCD25 group,there was no significant difference in the positive expression rates of CD117 and CD200 between the two groups(P＞0.05).The positive expression rates of CD56 and CD117 in the high IGF-Ⅰ group were higher than those in the low IGF-Ⅰ group(P＜0.05),and there was no significant difference in the positive expression rate of CD200 between the two groups(P＞0.05).Serum sCD25 and IGF-Ⅰ levels in the remission group were significantly lower than those in the non remission group(P＜0.05).ROC curve analysis showed that,the area under the curve(AUC)for evaluating the efficacy of newly diagnosed MM patients using serum sCD25 and IGF-Ⅰ detection alone and in combination were 0.748,0.775 and 0.832,respectively,and the AUC for combined detection was greater than that for each indicator detected separately.The results of multivariate Logistic regression model showed that elevated serum sCD25 level,elevated serum IGF-Ⅰ level and MM stage Ⅲ were independent risk factors affecting the efficacy of newly diagnosed MM patients(P＜0.05).Conclusion:Serum sCD25 and IGF-Ⅰ levels are closely related to the disease stage and therapeutic efficacy of newly diagnosed MM patients.Combined detection has a high evaluation value for efficacy and can be used as an important evaluation index affecting efficacy.

Aim To investigate the role of triggering receptor expressed on myeloidcells 2(TREM2)in syn-aptic plasticity induced by cocaine addiction.Methods C57BL/6J mice and Trem2 knockout mice were uti-lized in this study to evaluate the alterations in postsyn-aptic density protein 95(PSD-95)and synapsin 1(SYN1)within the cortex and hippocampus of co-caine-addicted mice by using immunological tech-niques.Results HE staining and Nissl staining showed increased neuronal damage in the hippocampus and cortex of mice after cocaine addiction.The results of immunohistochemistry and fluorescence of PSD-95 and SYN1 were consistent with the expression trend of Western blot.In the wild type mouse model,the ex-pression level of PSD-95 in the hippocampus and cortex was lower than that in the saline group,and the ex-pression of SYN1 was higher than that in the saline group.In the knockout mouse model,the expression levels of PSD-95 and SYN1 in the hippocampus and cortex were significantly higher than those in the saline group after cocaine addiction.The expression levels of PSD-95 and SYN1 in the hippocampus and cortex of cocaine knockout mice were higher than those of co-caine wild type mice.Conclusion Cocaine addiction can change the synaptic plasticity,and TREM2 plays a regulatory role in the synaptic plasticity of hippocampus and cortex in mice with cocaine injury.TREM2 is ex-pected to be a new target for studying the mechanism of cocaine addiction.

Objective Vascular dementia(VD)is a common cognitive dysfunction associated with cerebrovascular disease.This study is aimed at investigating the therapeutic effect of anisodine hydromide(AH)on VD and the potential antioxidative stress mechanisms involved.Methods A VD model was established in Sprague-Dawley(SD)rats through permanent bilateral common carotid artery occlusion.The rats were divided into a sham group,a VD model group,and AH treatment groups receiving AH at low,medium,or high doses(n=4).The neurological function of the rats in each group was evaluated using the Bederson scale,and limb coordination ability was assessed using the pole climbing test.Superoxide dismutase(SOD)and malondialdehyde(MDA)levels in the serum and brain were measured by enzyme-linked immunosorbent assay(ELISA)to assess the level of oxidative stress.In addition,apoptosis was assessed by TUNEL assay,and reactive oxygen species(ROS)levels in neuronal cells were determined using dichloro-dihydro-fluorescein diacetate(DCFH-DA)probe.The potential mechanism of action of AH on M receptors was investigated using M1-M5 inhibitors.Results Compared with the sham group,the nerve function and limb coordination of rats in the VD model group were significantly impaired(P＜0.01),and the SOD levels were significantly decreased in the serum([100.70±18.95]U/mL vs.[44.22±7.11]U/mL,P＜0.001)and the brain([131.77±8.34]U/mg vs.[84.39±4.10]U/mg,P＜0.01),MDA levels were significantly increased in the serum([12.03±1.01]nmol/mL vs.[17.74±1.00]nmol/mL,P＜0.001)and the brain([4.41±0.30]nmol/mg vs.[6.17±0.70]nmol/mg,P＜0.05).AH treatment significantly improved the neurological function and limb coordination ability of VD rats.In comparison with the VD group,the high-dose AH treatment group,in particular,exhibited the most significant increase in SOD levels in the serum([44.22±7.11]U/mL vs.[98.67±0.86]U/mL,P＜0.001)and the brain([84.39±4.10]U/mg vs.[162.83±17.36]U/mg,P＜0.001),and the most significant decrease in MDA levels in the serum([17.74±1.00]nmol/mL vs.[6.68±0.06]nmol/mL,P＜0.001)and the brain([6.17±0.70]nmol/mg vs.[3.96±0.77]nmol/mg,P＜0.01).AH also reduced the number of TUNEL positive cells(P＜0.01)in a dose-dependent manner.The percentage of apoptotic cells was(36.10±9.07)％,(9.60±5.63)％,and(3.43±0.92)％,respectively,for AH treatment at low,medium,and high concentrations,indicating that AH had an inhibitory effect on apoptosis.According to findings from the in vitro experiments,AH treatment reduced the MDA content(P＜0.01),increased the SOD activity(P＜0.01),and decreased the ROS levels of HT22 and NSC-34 cells in a dose-dependent manner.M2 receptor inhibitors could reduce the ROS level in oxidative stress injury,suggesting that AH,as an M receptor antagonist,might exert its effect by inhibiting the M2 receptor.Conclusion AH modulates SOD and MDA levels and reduces oxidative stress injury,thereby improving neurological function and limb coordination and showing potential therapeutic effects in VD.The neuroprotective effects of AH may be related to its antioxidative stress and antiapoptotic mechanisms,and the M2 receptor may be a potential target of its actions.These findings provide an important theoretical basis for the development of new therapeutic strategies for VD.