AIM:This study investigated the role of solute carrier family 7 member 11(SLC7A11)in sul-fasalazine(SAS)-induced ferroptosis in acute myeloid leukemia(AML)cells,focusing on the inhibitory effect of nuclear factor E2-related factor 2(NRF2)nuclear translocation-mediated activation of SLC7A11 on ferroptosis and its underlying mechanisms.METHODS:SAS-induced proliferation in AML cell lines,Kasumi-1 and THP-1,was assessed using the MTS assay.Cell death inhibitors were employed to determine the mode of cell death.Lipid reactive oxygen species(ROS)levels were measured by flow cytometry;Fe2+,malonodialdehyde(MDA),glutathione(GSH)levels,and glutathione per-oxidase 4(GPX4)activity were assessed using micromethods.Quantitative PCR(qPCR)was performed to evaluate changes in SLC7A11 mRNA during SAS-induced ferroptosis,while Western blot measured SLC7A11 and GPX4 protein levels.Moreover,Western blot assessed NRF2 nuclear translocation post-SAS treatment.The NRF2 inhibitor ML385 was used to validate these effects.SLC7A11 mRNA and protein levels were then measured following combined SAS and ML385 treatment via qPCR and Western blot.Cell viability and ferroptosis-related indices were evaluated under the same treatment conditions.Furthermore,a shRNA vector targeting SLC7A11 was constructed to assess changes in cell viability and ferroptosis markers after SLC7A11 knockdown with SAS.GPX4 protein levels were examined following SLC7A11 knockdown.RESULTS:SAS significantly inhibited the proliferation of Kasumi-1 and THP-1 cells at 200 μmol/L and 300 μmol/L,respectively(P<0.05).Only ferroptosis inhibitors(Fer-1 and DFO)significantly reversed SAS-induced cy-totoxicity(P<0.01).SAS increased lipid ROS,Fe2+,and MDA levels(P<0.01),while reducing GSH and GPX4 activity(P<0.01).The mRNA and protein expressions of SLC7A11 increased during SAS-induced ferroptosis(P<0.01),where-as GPX4 protein decreased significantly(P<0.01).SAS significantly increased the nuclear-to-cytoplasmic NRF2 ratio(P<0.01),which decreased upon co-treatment with ML385(P<0.05).Following SAS and ML385 co-treatment,both SLC7A11 mRNA and protein levels were downregulated(P<0.01).This combination treatment further reduced AML cell viability(P<0.01),an effect reversed by Fer-1 and DFO(P<0.01).Compared with SAS alone,the combination of SAS and ML385 significantly increased lipid ROS,Fe2+,and MDA while reducing GSH levels and GPX4 activity(P<0.01).SLC7A11 knockdown was successfully achieved.Compared with the NC shRNA group,SLC7A11 knockdown cells showed significantly decreased viability after SAS treatment,which was reversed by Fer-1 and DFO(P<0.01).Lipid ROS,Fe2+,and MDA content were significantly increased(P<0.01),and GSH and GPX4 were substantially decreased(P<0.05).Moreover,GPX4 protein expression was considerably reduced after SLC7A11 knockdown(P<0.01).CONCLUSION:SAS induces ferroptosis in AML cells.It promotes the nuclear translocation of NRF2 protein,which activates SLC7A11 ex-pression.Inhibition of NRF2 or downregulation of SLC7A11 sensitizes AML cells to SAS-induced ferroptosis.

AIM:This study investigated the role of solute carrier family 7 member 11(SLC7A11)in sul-fasalazine(SAS)-induced ferroptosis in acute myeloid leukemia(AML)cells,focusing on the inhibitory effect of nuclear factor E2-related factor 2(NRF2)nuclear translocation-mediated activation of SLC7A11 on ferroptosis and its underlying mechanisms.METHODS:SAS-induced proliferation in AML cell lines,Kasumi-1 and THP-1,was assessed using the MTS assay.Cell death inhibitors were employed to determine the mode of cell death.Lipid reactive oxygen species(ROS)levels were measured by flow cytometry;Fe2+,malonodialdehyde(MDA),glutathione(GSH)levels,and glutathione per-oxidase 4(GPX4)activity were assessed using micromethods.Quantitative PCR(qPCR)was performed to evaluate changes in SLC7A11 mRNA during SAS-induced ferroptosis,while Western blot measured SLC7A11 and GPX4 protein levels.Moreover,Western blot assessed NRF2 nuclear translocation post-SAS treatment.The NRF2 inhibitor ML385 was used to validate these effects.SLC7A11 mRNA and protein levels were then measured following combined SAS and ML385 treatment via qPCR and Western blot.Cell viability and ferroptosis-related indices were evaluated under the same treatment conditions.Furthermore,a shRNA vector targeting SLC7A11 was constructed to assess changes in cell viability and ferroptosis markers after SLC7A11 knockdown with SAS.GPX4 protein levels were examined following SLC7A11 knockdown.RESULTS:SAS significantly inhibited the proliferation of Kasumi-1 and THP-1 cells at 200 μmol/L and 300 μmol/L,respectively(P<0.05).Only ferroptosis inhibitors(Fer-1 and DFO)significantly reversed SAS-induced cy-totoxicity(P<0.01).SAS increased lipid ROS,Fe2+,and MDA levels(P<0.01),while reducing GSH and GPX4 activity(P<0.01).The mRNA and protein expressions of SLC7A11 increased during SAS-induced ferroptosis(P<0.01),where-as GPX4 protein decreased significantly(P<0.01).SAS significantly increased the nuclear-to-cytoplasmic NRF2 ratio(P<0.01),which decreased upon co-treatment with ML385(P<0.05).Following SAS and ML385 co-treatment,both SLC7A11 mRNA and protein levels were downregulated(P<0.01).This combination treatment further reduced AML cell viability(P<0.01),an effect reversed by Fer-1 and DFO(P<0.01).Compared with SAS alone,the combination of SAS and ML385 significantly increased lipid ROS,Fe2+,and MDA while reducing GSH levels and GPX4 activity(P<0.01).SLC7A11 knockdown was successfully achieved.Compared with the NC shRNA group,SLC7A11 knockdown cells showed significantly decreased viability after SAS treatment,which was reversed by Fer-1 and DFO(P<0.01).Lipid ROS,Fe2+,and MDA content were significantly increased(P<0.01),and GSH and GPX4 were substantially decreased(P<0.05).Moreover,GPX4 protein expression was considerably reduced after SLC7A11 knockdown(P<0.01).CONCLUSION:SAS induces ferroptosis in AML cells.It promotes the nuclear translocation of NRF2 protein,which activates SLC7A11 ex-pression.Inhibition of NRF2 or downregulation of SLC7A11 sensitizes AML cells to SAS-induced ferroptosis.

Objective:To investigate effect of SARI expression induced by IFN-β on proliferation and apoptosis of acute myelo-blastic leukemia(AML)cells,and to explore its potential regulatory molecules.Methods:qPCR and Western blot were used to screen AML cells with low SARI expression as experimental cell lines.AML cells were treated with different concentrations of IFN-β,and expression of SARI was detected by qPCR and Western blot at different time to select appropriate concentration and time of IFN-β.RNA-Seq transcriptome sequencing and KEGG enrichment analysis were used to preliminarily screen potential regulatory molecules of IFN-β-induced SARI expression in AML cells.AML cells were treated with corresponding molecular inhibitors combined with IFN-β,cell proliferation was detected by MTS assay,and apoptosis was detected by flow cytometry.To clear this molecule was involved in IFN-β-induced SARI expression on AML cell proliferation and apoptosis.Results:SARI expression in HL60 and NB4 cells were rela-tively decreased,so they were selected as experimental cell lines.After treatment with 1 ng/ml IFN-β for 12 h,SARI expression in AML cells was increased,cell proliferation was inhibited and apoptosis were increased.STAT1 was screened as a potential regulatory mole-cule for IFN-β-induced SARI expression.After inhibiting STAT1,effects of IFN-β on SARI expression,proliferation inhibition and apop-tosis promotion of AML cells were reversed significantly.Conclusion:IFN-β can promote SARI expression in AML cells by STAT1,in-hibit cell proliferation and promote apoptosis.

Objective:To investigate the efficacy and safety of neoadjuvant therapy with trastuzumab and pertuzumab combined with taxane and platinum drugs (TCbHP) regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer.Methods:A retrospective case series study was conducted. The clinical data of HER2-positive breast cancer patients who received neoadjuvant therapy with 21-day TCbHP regimen and completed subsequent surgery in 11 tertiary-level hospitals in Hebei Province from June 2019 to December 2021 were retrospectively analyzed, and the total pathological complete remission (tpCR) rate, the incidence of grade ≥3 adverse events, and the completion rate of the established regimen were statistically analyzed.Results:A total of 78 female patients were included and the median age [ M ( Q1, Q3)] was 54.0 years (48.5 years, 57.5 years). The tpCR rate was 64.1% (50/78). Subgroup analysis showed that the tpCR rate in the HER2 immunohistochemistry (IHC)+++ group was higher than that in the HER2 IHC++ and fluorescence in situ hybridization-positive group [68.6% (48/70) vs. 25.0% (2/8)], and the difference was statistically significant ( χ2 = 4.18, P = 0.041); the tpCR rate in the hormone-receptor negative group was higher than that in the hormone-receptor positive group [81.8% (27/33) vs. 51.1% (23/45)], and the difference was statistically significant ( χ2 = 7.80, P = 0.005); the tpCR rate in the albumin-bound paclitaxel group was higher than that in the docetaxel group [72.3% (34/47) vs. 48.3% (14/29)], and the difference was statistically significant ( χ2 = 4.46, P = 0.035). The incidence of ≥ grade 3 adverse reactions was 12.8% (10/78) in 78 patients, and the completion rate of the established regimen was 92.3% (72/78). Conclusions:Neoadjuvant therapy with TCbHP regimen for HER2-positive breast cancer shows a definite efficacy, good safety and tolerance.

Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target for breast cancer in recent years. The emergence of targeted drugs represented as trastuzumab has drastically improved the prognosis of HER2-positive breast cancer patients. Antibody-drug conjugates (ADC) such as trastuzumab deruxtecan (T-DXd) have shown the obvious therapeutic efficacies in breast cancer with HER2 low expression recently, which has become a research hotpot. With the deepening of the research, new views of the detection of HER2 and the molecular subtypes of breast cancer are proposed, besides, the concept of ultra-low HER2 expression is also proposed by some scholars. Several studies have explored the application of ADC and new treatments in HER2 low expression breast cancer. This paper reviews the definition, the detection and determination, clinicopathologic characteristics and treatment progress of breast cancer with HER2 low expression.

Objective To construct a predictive model for septic shock based on the propensity score matching (PSM) method and validate its effectiveness. Methods A total of 114 patients with sepsis were enrolled as study objects, and were divided into septic shock group (40 patients) and sepsis group (74 patients) according to whether they developed septic shock. PSM was performed with a ratio of septic shock to sepsis of 1∶2, resulting in the inclusion of 30 patients in the septic shock group and 60 patients in the sepsis group after matching. The levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), serum amyloid A (SAA), soluble endothelial protein C receptor (sEPCR), endothelial cell-specific molecule 1 (ESM-1), clusterin (CLU), and the Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score and Sequential Organ Failure Assessment (SOFA) score at admission were compared between the two groups. Cox proportional hazards regression analysis was used to identify the factors influencing septic shock, and a predictive model for septic shock was constructed and internally validated using the receiver operating characteristic (ROC) curve. Kaplan-Meier survival curves were plotted to analyze the differences in survival prognosis among patients with different expression levels of the indicators. Results After matching, there were no statistically significant differences in general information between the two groups (P>0.05). At admission, the septic shock group had higher levels of serum PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of serum CLU compared with the sepsis group (P < 0.05). Cox regression analysis showed that PCT, CRP, SAA, IL-6, sEPCR, ESM-1, APACHE Ⅱ score, and SOFA score were independent risk factors for septic shock (P < 0.05), while CLU was an independent protective factor (P < 0.05). The predictive model for septic shock, constructed based on these factors, showed an internal validation accuracy of 94.44%, an area under the curve of 0.950, a sensitivity of 93.33%, and a specificity of 96.67%. Dead patients had higher levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of CLU at admission compared with survivors (P < 0.05). Compared with patients with low expression levels or low scores, patients with high expression levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and high APACHE Ⅱ and SOFA scores had higher fatality rates, while patients with high CLU expression levels had a lower fatality rate (P < 0.05). Conclusion The serum biomarkers including PCT, CRP, SAA, IL-6, sEPCR, ESM-1, CLU, and the APACHE Ⅱ and SOFA scores in sepsis patients are closely related to the occurrence of septic shock and survival prognosis. The predictive model constructed by combining these indicators can accurately predict the occurrence of septic shock.

Objective:To explores the relationship between self-efficacy and marital adjustment in infertile couples based on Actor-Partner Interdependence Model (APIM) .Methods:This study was a cross-sectional survey. A total of 310 infertile couples who underwent in vitro fertilization-embryo transfer cycle treatment in Reproductive Center of Peking University Third Hospital from January to April 2022 were selected as the research objects by the convenient sampling method. General Self-Efficacy Scale and Locke-Wallace Marital Adjustment Test were used to investigate. The relationship between self-efficacy and marital adjustment of infertile couples was analyzed by Pearson correlation analysis and APIM. A total of 310 groups of questionnaires were distributed (1 group was 1 couple) , and 293 groups of effective questionnaires were collected, with an effective recovery rate of 94.5%. Results:The self-efficacy scores of infertile couples were (25.08±5.54) for wives and (27.08±5.35) for husbands, and the self-efficacy scores of wives were lower than those of husbands ( P<0.01) . In the score of marital adjustment, the wives scored (109.39±23.13) and the husbands scored (111.99±20.87) . The APIM analysis results show that in terms of subjective effects, the self-efficacy of both infertile couples could affect their own marital adjustment (β=0.166, 0.408; P<0.01) . In terms of object effects, the husbands' self-efficacy could affect the wives' marital adjustment (β=0.117, P<0.05) . Conclusions:The self-efficacy of infertile couples undergoing in vitro fertilization-embryo transfer cycle treatment is at the middle level, and the marriage adjustment is generally good. The self-efficacy of couples is closely related to their own marital adjustment, and the self-efficacy of husbands can also positively affect the wifes' marital adjustment. In clinical work, infertile couples should be regarded as a whole, focusing on the binary interaction between both parties, and developing targeted measures to help infertile couples improve their self-efficacy, thereby improving marital adjustment, improving health outcomes, and stabilizing family relationships.

Objective:To explore the effectiveness, safety and cost between urinary follicle stimulating hormone (uFSH) and recombinant follicle stimulating hormone (rFSH) in controlled ovarian stimulation (COS) in China.Methods:Data were collected from 16 reproductive centers in China covering oocytes collection time from May 1, 2015 to June 30, 2018. Eligible patients were over 18 years old, adopting COS with uFSH (uFSH group) or rFSH (rFSH group) as start gonadotropins (Gn), and using in vitro fertilization (IVF) and (or) intracytoplasmic sperm injection for fertilisation, excluding frozen embryo recovery cycle. Generalised estimating equation was used to address the violation of independency assumption between cycles due to multiple IVF cycles for one person and clustering nature of cycles carried out within one center. Controlling variables included age, body mass index, anti-Müllerian hormone level, cause of infertility, ovulation protocol, type of fertilisation, number of embryos transferred, number of days of Gn use.Results:Totally 102 061 cycles met eligibility criteria and were included in the analyses. In terms of effectiveness, after controlling relevant unbalanced baseline characteristics, compared with rFSH group, the high oocyte retrieval (>15 oocytes was considered high retrieval) rate of uFSH group significantly decreased in gonadotropin-releasing hormone agonist protocol ( OR=0.642, P<0.01) and in gonadotropin-releasing hormone antagonist protocol ( OR=0.556, P=0.001), but the clinical pregnancy rate per transfer cycle and the live birth rate per transfer cycle significantly increased ( OR=1.179, OR=1.169, both P<0.01) in both agonist and antagonist protocols. For safety, multiple analysis result demonstrated that in the agonist protocol, compared with rFSH group, the incidence of moderate to severe ovarian hyperstimulation syndrome of uFSH group significantly decreased ( OR=0.644, P=0.002). The differences in ectopic pregnancy rate and multiple pregnancy rate between the uFSH and rFSH groups were not significant ( P=0.890, P=0.470) in all patients. In terms of cost, compared with rFSH group, the uFSH group had lower total Gn costs for each patient ( P<0.01). Conclusion:For patients who underwent COS, uFSH has better safety, and economic profiles over rFSH in China.

Objective:To investigate the clinical efficacy of posterolateral approach combined with anteromedial approach in the treatment of trimalleolus fracture.Methods:A retrospective analysis was performed of the 20 patients who had been admitted to The Second Department of Orthopedics, The First People's Hospital of Tianshui for trimalleolus fractures from January 2016 to August 2020. They were 16 men and 4 women, aged from 20 to 70 years (average, 49.6 years). The lateral malleolus, posterior malleolus and medial malleolus were treated with reduction and internal fixation using the posterolateral approach combined with the anteromedial approach. Postoperative complications were observed, and the foot function was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and pain visual analog scale (VAS).Results:In this cohort, the operation time ranged from 85 to 115 minutes, averaging 88.4 minutes and the intraoperative blood loss from 50 to 600 mL, averaging 120 mL. All patients were followed up for 12 to 20 months (mean, 14.5 months). The fracture healing time ranged from 3.2 to 5.4 months, averaging 3.8 months. Follow-ups observed no such complications as infection or necrosis of surgical incision, failure of internal fixation, nonunion, or malunion. The AOFAS ankle-hindfoot score at 12 months after operation (87.8±6.4) was significantly higher than that before operation (32.3±4.9) ( t=29.454, P<0.001); as for VAS, one case scored 0, 13 cases 1 to 3 points and 6 cases 4 points. Conclusion:In the treatment of trimalleolus fracture, a combination of posterolateral approach and anteromedial approach can lead to definitely positive efficacy because of a significant reduction in operation time, intraoperative bleeding and postoperative complications.

Transcranial direct current stimulation (tDCS) is a well-tolerated, safe and noninvasive physical brain stimulation method, which has been widely used in the treatment of some common mental disorders and neurological diseases and has achieved certain clinical effects. It is necessary to develop expert consensus on clinical treatment to improve the use norms in related fields. According to the clinical research published before August 2021 and the method of evidence-based medicine, we published an expert consensus on tDCS in the treatment of depressive disorders, schizophrenia, substance use-related disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism, anxiety disorders, post-traumatic stress disorder, sleep disorders, pain, Parkinson′s disease, stroke, and epilepsy. The consensus also introduced the safety and efficacy of the clinical use of tDCS, and standardized the treatment process and operation technology, aiming to provide guidance for the clinical application of tDCS and promote the standardized development of this treatment technology in the future.