The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Objective To explore the protective effect and underlying mechanism of roxadustat(FG-4592),hypoxia-inducible factor-α(HIF-α)prolyl hydroxylase inhibitor,on brain injury caused by heat stroke(HS).Methods A total of 140 male C57BL/6J mice(6～8 weeks old,weighing 18～22 g)were subjected,and 40 of them were randomly divided into HS group,and low-,medium-and high-dose roxadustat groups(LD,MD and HD groups,5,10 and 20 mg/kg),with 10 mice in each group.The 24-hour survival rate was observed to determine the optimal dosage of roxadustat after modeling.Additionally,the remaining 100mice were randomly allocated to normal control(Control)group,roxadustat(FG-4592)group,HS group,and roxadustat+HS(FG-4592+HS)group,with 25 mice in each.Heat shock was inflicted to establish mouse model of HS.Modified neurological severity score(mNSS)was used to assess neurological function.HE staining of brain sections was performed to examine pathological damage,and Fluoro-Jade C staining was applied to observe neuronal degeneration.The activity of total superoxide dismutase(SOD)and content of malondialdehyde(MDA)in brain tissue were measured to assess oxidative stress.Transmission electron microscopy was employed to visualize mitochondrial damage.Western blotting was performed to assess the protein levels of Caspase-3,Cleaved Caspase-3,Mfn1,Mfn2,Opa1,Fis1,HIF-1α,HO-1 and p-Drp1(Ser616)/Drp1 ratio in the cerebral cortex.Results Compared to the HS group,FG-4592 significantly improved the survival rate of HS mice within 24 h,with the MD group showing the highest survival rate.Compared to the Control group,the HS group showed an increase in mNSS score(P＜0.05),an elevation in the MDA content in the cerebral cortex(P＜0.05),and a decrease in total SOD activity in the cerebral cortex(P＜0.05);HE staining revealed pathological damage in the cerebral cortex,and Fluoro-Jade C staining displayed obvious neuronal degeneration in the cerebral cortex;Electron microscopy revealed obvious mitochondrial structural damage in the cerebral cortex tissue;The protein expression of Caspase-3,Cleaved Caspase-3,Fis1,HIF-1α,HO-1 and p-Drp1(Ser616)/Drp1 ratio was increased(P＜0.05),while that of Mfn1,Mfn2,and Opa1 was decreased(P＜0.05).Pretreatment with FG-4592 significantly reduced the mNSS score in HS mice(P＜0.05),decreased MDA content(P＜0.05),and enhanced total SOD activity(P＜0.05).Additionally,FG-4592 pretreatment improved pathological damage in the cerebral cortex,reduced neuronal degeneration,and mitigated mitochondrial structural damage.Furthermore,it decreased the protein levels of Caspase-3,Cleaved Caspase-3,Fis1 and p-Drp1(Ser616)/Drp1 ratio(P＜0.05),while increased the levels of Mfn1,Mfn2,Opa1,HIF-1α,and HO-1(P＜0.05).Conclusion Roxadustat regulates the balance between mitochondrial fission and fusion,reduces mitochondrial structural damage,oxidative stress and apoptosis,and alleviates heat stroke-induced brain injury.

Objective To establish a prediction model for in-hospital mortality risk in patients with sepsis-induced coagulopathy based on LASSO regression.Methods Patients with sepsis-induced coagulopathy ad-mitted to intensive care unit(ICU)at Beth Israel Deaconess Medical Center during 2008 to 2019 were selected from the Medical Information Market for Intensive Care(MIMIC)-Ⅳ database(version 2.1)for retrospective study.The study subjects were randomly divided into modeling group and verification group,and the feature variables were screened by LASSO regression.The feature variables were analyzed by multivariate Logistic re-gression to determine independent risk factors,and the nomogram prediction model was established at the same time.The model performance was evaluated by drawing calibration curve and receiver operating charac-teristic(ROC)curve,as well as decision curve analysis.Results A total of 4 994 patients with sepsis-induced coagulopathy admitted to ICU for the first time were enrolled in this study.They were randomly divided into a model group(n=3 495)and a validation group(n=1 499)at a ratio of 7:3.Multivariate Logistic regres-sion analysis showed that age,mean respiratory rate,mean corpuscular hemoglobin concentration,red blood cell count,platelet count,prothrombin time,anion gap,acute physiological score Ⅲ and acute kidney injury were independent risk factors for in-hospital mortality of patients with sepsis-induced coagulopathy.Based on the above independent risk factors,a nomographic prediction model was constructed.The area under the ROC curve and 95％confidence interval of the nomogram in the modeling group and validation group were 0.864(0.849-0.880)and 0.877(0.852-0.901),respectively.The sensitivity was 0.795 and 0.763,and the speci-ficity was 0.779 and 0.843,respectively.The calibration curve suggested that the predicted probability was ba-sically consistent with the actual probability,and the decision curve analysis showed that it had good clinical net benefits within a wide range of threshold.Conclusion The nomogram model based on MIMIC-Ⅳ database has good predictive value for predicting the in-hospital mortality of patients with sepsis-induced coagulopathy and can be used to guide clinical work.

Objective:To assess the clinical effectiveness and safety of Omalizumab for treating pediatric allergic asthma in real world in China.Methods:The clinical data of children aged 6 to 11 years with allergic asthma who received Omalizumab treatment in 17 hospitals in China between July 6, 2018 and September 30, 2020 were retrospectively analyzed.Such information as the demographic characteristics, allergic history, family history, total immunoglobulin E (IgE) levels, specific IgE levels, skin prick test, exhaled nitric oxide (FeNO) levels, eosinophil (EOS) counts, and comorbidities at baseline were collected.Descriptive analysis of the Omalizumab treatment mode was made, and the difference in the first dose, injection frequency and course of treatment between the Omalizumab treatment mode and the mode recommended in the instruction was investigated.Global Evaluation of Treatment Effectiveness (GETE) analysis was made after Omalizumab treatment.The moderate-to-severe asthma exacerbation rate, inhaled corticosteroid (ICS) dose, lung functions were compared before and after Omalizumab treatment.Changes in the Childhood Asthma Control Test (C-ACT) and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) results from baseline to 4, 8, 12, 16, 24, and 52 weeks after Omalizumab treatment were studied.The commodity improvement was assessed.The adverse event (AE) and serious adverse event (SAE) were analyzed for the evaluation of Omalizumab treatment safety.The difference in the annual rate of moderate-to-severe asthma exacerbation and ICS reduction was investigated by using t test.The significance level was set to 0.05.Other parameters were all subject to descriptive analysis.A total of 200 allergic asthma patients were enrolled, including 75.5% ( n=151) males and 24.5% ( n=49) females.The patients aged (8.20±1.81) years. Results:The median total IgE level of the 200 patients was 513.5 (24.4-11 600.0) IU/mL.Their median treatment time with Omalizumab was 112 (1-666) days.Their first dose of Omalizumab was 300 (150-600) mg.Of the 200 cases, 114 cases (57.0%) followed the first Omalizumab dosage recommended in the instruction.After 4-6 months of Omalizumab treatment, 88.5% of the patients enrolled ( n=117) responded to Omalizumab.After 4 weeks of treatment with Omalizumab, asthma was well-controlled, with an increased C-ACT score [from (22.70±3.70) points to (18.90±3.74) points at baseline]. Four-six months after Omalizumab administration, the annual rate of moderate-to-severe asthma exacerbation had a reduction of (2.00±5.68) per patient year( t=4.702 5, P<0.001), the median ICS daily dose was lowered [0 (0-240) μg vs. 160 (50-4 000) μg at baseline] ( P<0.001), the PAQLQ score was improved [(154.90±8.57) points vs. (122.80±27.15) points at baseline], and the forced expiratory volume in one second % predicted (FEV 1%pred) was increased [(92.80±10.50)% vs. (89.70±18.17)% at baseline]. In patients with available evaluations for comorbidities, including allergic rhinitis, atopic dermatitis or eczema, urticaria, allergic conjunctivitis and sinusitis, 92.8%-100.0% showed improved symptoms.A total of 124 AE were reported in 58 (29.0%) of the 200 patients, and the annual incidence was 0(0-15.1) per patient year.In 53 patients who suffered AE, 44 patients (83.0%) and 9 patients (17.0%) reported mild and moderate AE, respectively.No severe AE were observed in patients.The annual incidence of SAE was 0(0-1.9) per patient year.Most common drug-related AE were abdominal pain (2 patients, 1.0%) and fever (2 patients, 1.0%). No patient withdrew Omalizumab due to AE. Conclusions:Omalizumab shows good effectiveness and safety for the treatment of asthma in children.It can reduce the moderate-to-severe asthma exacerbation rate, reduce the ICS dose, improve asthma control levels, and improve lung functions and quality of life of patients.

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.

We reported a case of microcephaly-capillary malformation(MIC-CAP)caused by STAMBP gene variant,in order to improve the clinical diagnosis and treatment.The patient is a 3-month-old male with recurrent convulsions and the main clinical manifestations are multiple forms of seizures,microcephaly,multiple small capillary malformations in the skin,and generalized hypotonia.The genetic test showed that a heterozygous variant in the STAMBP gene was present in the child.Both parents were heterozygous carriers.He was administrated various anti-seizure medications and ketogenic diet,but still had frequent seizures.He then underwent corpus callosotomy,and was followed up until he was 4 years and 10 months old.The post operational outcome was grade IV on Engel's classification.Based on the clinical data of 22 patients in literature,in addition to severe psychomotor retardation,microcephaly,and cutaneous capillary malformations,early-onset drug-refractory epilepsy is also a major feature of MIC-CAP syndrome,which is clinically rare and has a poor prognosis;Callosotomy may help to reduce seizures in the short term.However,the long-term outcome is poor.STAMBP gene is the main responsible gene for this syndrome.

{L-End}Objective To investigate the effect of motorcycle exhaust (ME) on the level of oxidative stress in different parts of respiratory tract epithelial cells. {L-End}Methods BEAS-2B and A549 cells in logarithmic growth phase were randomly divided into control group, low- and high-dose groups. The two kinds of cells growing on the membrane of Transwell inserts were treated with air-liquid interface (ALI) exposure technique for 60 minutes. The cells in the low- and high- dose groups were treated with diluted gas with the volume ratio of ME to clean air of 1∶20 and 1∶10, respectively, while the cells in the control group were treated with clean air. Cells were collected to detect their relative survival rate using CCK-8 method after exposure. And the levels of malondialdehyde, glutathione and the activity of superoxide dismutase (SOD) of the cells were detected using colorimetry. {L-End}Results The ME exposure dose affected the relative survival rate of cells (P<0.01), which showed a downward trend with the increasing ME exposure doses (all P<0.05). However, there was no significant difference in the main effect of cell types and the interaction effect of ME exposure dose and cell type (all P>0.05). There was a significant interaction between ME exposure dose and cell type in the level of glutathione and the activity of SOD (all P<0.01), and the level of malondialdehyde was a significant main effect of cell type (P<0.01). There was no significant difference in the glutathione level and SOD activity between the low-dose group and the control group (all P>0.05), while the glutathione level and SOD activity in high-dose group were higher than those in the control group and low-dose group in BEAS-2B cells (all P<0.05). The glutathione level decreased with increasing ME exposure dose in A549 cells (all P<0.05). Compared with the control group, the low-dose group had a significantly higher activity of SOD (P<0.05) in A549 cells. The SOD activity of A549 cells in high-dose group was lower than those in control group and low-dose group (all P<0.05). The level of malondialdehyde in A549 cells was higher than those in BEAS-2B cells(P<0.05). {L-End}Conclusion ME exposure can lead to changes in the production of oxidative stress biomarkers in respiratory tract epithelial cells. The oxidative stress response induced by ME exposure varies among respiratory tract epithelial cells from different regions.

Objective:To observe heart rate circadian rhythm in patients with chronic kidney disease (CKD) stage 5 and to analyze the effects of parathyroidectomy (PTX) on heart rate circadian rhythm in severe secondary hyperparathyroidism (SHPT) patients.Methods:A cross-sectional observation was performed in 213 patients with CKD stage 5 and 96 controls, and the patients were divided into those with severe SHPT (PTX group, n=70) and without severe SHPT (non-PTX group, n=143). Forty-six PTX patients were followed up prospectively. The baseline data were compared among these groups. Holter electrocardiogram was performed for each participant. Non-dipping heart rate was defined as night/day heart rate ratio greater than 0.9. Multiple linear regression analysis was used to analyze the related factors of heart rate circadian rhythm in patients with CKD stage 5. Results:The 24-hour, daytime and nighttime mean heart rate in patients with CKD stage 5 were all higher than those in controls, especially in PTX group (all P<0.05). The night/day heart rate ratios of controls and CKD stage 5 patients were (0.81±0.08) and (0.91±0.08) respectively ( P<0.01). Correlation analysis showed 24-hour and daytime or nighttime mean heart rate in patients with CKD stage 5 were positively correlated with serum levels of phosphorus and ln(alkaline phosphatase), while nighttime mean heart rate and night/day heart rate ratio were positively related with serum intact parathyroid hormone level. After adjusting with postoperative follow-up period (median time: 10.9 months), 24-hour and nighttime mean heart rate, and night/day heart rate ratio in PTX patients all decreased significantly (all P<0.01). Conclusions:Heart rate is increased and circadian rhythm is abnormal in patients with CKD stage 5, which are related with mineral and bone disorder. PTX significantly decreases 24-hour and nighttime mean heart rate in severe SHPT patients, and improves the heart rate circadian rhythm.

Objective:To carry out nurse-led evidence-based practices to reduce the incidence of pulmonary complications of patients after thoracic surgery.Methods:A multidisciplinary team was set up. The best evidence-based interventions were obtained by adopting evidence-based nursing procedures and were implemented in the clinical practice after localization. Based on the evidence, examination standards were established, and obstacles and promoting factors in the implementation process were evaluated. Then action strategies were formulated to regulate medical staff′s clinical practice. The patients ′ incidence of pulmonary complications, pulmonary function indicators, patient satisfaction and pulmonary rehabilitation knowledge and medical staff′s compliance with examination standards were compared before and after the application of the best evidence. Results:After the application of the best evidence, the incidence of pulmonary complications decreased from 18.2%(6/33) to 0 ( χ2 value was 4.264, P < 0.05). The pulmonary indicators of FEV1/FVC, breath holding test and six minute walking test were (76.1±3.3)%, (27.2±1.5) s and (522.6±13.0) m before the application of best evidence, respectively, and (82.7±2.8)%, (31.0±5.3) s and (561.5±16.4) m after the application of best evidence, respectively. The differences were all statistically significant ( t value was -8.600, -3.007, 10.542, P < 0.01). Meanwhile the medical staff ′s compliance with the 10 examination standards were all increased to over 85% after the implementation of the best evidence ( χ2 value was 16.834-64.000, P<0.01). Patients ′ pulmonary rehabilitation knowledge was 24.2%(8/33) and 83.9% (26/31) respectively before and after the application of the best evidence, the difference was statistically significant ( χ2 value was 22.823, P<0.01). Patients ′ satisfaction improved. Conclusions:By applying the best evidence, nurse-led multidisciplinary team can reduce the incidence of pulmonary complications and improve the care quality for patients after thoracic surgery.

Overexpression of exogenous lineage-determining factors succeeds in directly reprogramming fibroblasts to various cell types. Several studies have reported reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs). CRISPR/Cas9-mediated gene activation is a potential approach for cellular reprogramming due to its high precision and multiplexing capacity. Here we show lineage reprogramming to iCPCs through a dead Cas9 (dCas9)-based transcription activation system. Targeted and robust activation of endogenous cardiac factors, including GATA4, HAND2, MEF2C and TBX5 (G, H, M and T; GHMT), can reprogram human fibroblasts toward iCPCs. The iCPCs show potentials to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells . Addition of MEIS1 to GHMT induces cell cycle arrest in G2/M and facilitates cardiac reprogramming. Lineage reprogramming of human fibroblasts into iCPCs provides a promising cellular resource for disease modeling, drug discovery and individualized cardiac cell therapy.