Objective To explore the mechanism by which gentiopicroside (GPS) prevents macrophage-mediated hepatic fibrosis by regulating the macrophage migration inhibitory factor (MIF)-secreted phosphoprotein 1 (SPP1) signaling pathway in hepatic stellate cells. Methods LX-2 cells were divided into control group, transforming growth factor β(TGF-β) group, and TGF-β combined with GPS (25, 50, 100, 150 μmol/mL) groups. Cell proliferation was detected by EDU assay, cell invasion was assessed by Transwell^TM assay, and the protein expressions of α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) were measured by Western blot. M1-type macrophage-conditioned medium (M1-CM) was used to treat LX-2 cells in the TGF-β group and TGF-β combined with GPS group. The concentrations of inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1) in the cell supernatant, as well as cell proliferation, invasion ability, and the expressions of α-SMA and COL1A1 were detected. Bioinformatics analysis was performed to identify the target intersections of GPS, hepatic fibrosis, and macrophage-related genes. Drug affinity responsive target stability (DARTS) experiments and Western blot were used to verify the regulatory effect of GPS on MIF. Furthermore, LX-2 cells were divided into control group, TGF-β group, TGF-β combined with M2-CM group, TGF-β and oe-NC combined with M2-CM group, and TGF-β and oe-MIF combined with M2-CM group to analyze the concentrations of iNOS and Arg1 in the cell supernatant, as well as changes in cell proliferation, invasion, and the expressions of α-SMA and COL1A1. LX-2 cells were also divided into control group, TGF-β group, TGF-β combined with oe-NC group, TGF-β combined with oe-MIF group, and TGF-β and oe-MIF combined with GPS group to determine the protein expressions of MIF and SPP1 by Western blot. A rat model of hepatic fibrosis was constructed to explore the potential therapeutic effects of GPS on hepatic fibrosis in vivo. Results Compared with the control group, the proliferation and invasion abilities of LX-2 cells in the TGF-β group were increased, and the protein expressions of α-SMA and COL1A1 were enhanced. GPS intervention inhibited the proliferation and invasion of LX-2 cells under TGF-β conditions and reduced the expressions of α-SMA and COL1A1. Compared with the control group, the concentration of iNOS in the cell supernatant of the TGF-β group was upregulated, while the concentration of Arg1 was decreased. M1-CM treatment further increased the concentration of iNOS, decreased the concentration of Arg1, and promoted cell proliferation and invasion, as well as upregulated the expressions of α-SMA and COL1A1 on the basis of TGF-β intervention. However, GPS could reverse the effects of M1-CM intervention. Bioinformatics analysis revealed that MIF was one of the target intersections of GPS, hepatic fibrosis, and macrophage-related genes, and GPS could target and inhibit its expression. Compared with the TGF-β group, after M2-CM intervention, the concentration of iNOS in the cell supernatant decreased, the concentration of Arg1 increased, the proliferation and invasion abilities of LX-2 cells were reduced, and the expressions of α-SMA and COL1A1 were weakened. However, overexpression of MIF reversed the effects of M2-CM intervention. Western blot results showed that compared with the control group, the protein expressions of MIF and SPP1 were enhanced in the TGF-β group. Overexpression of MIF further enhanced the expressions of MIF and SPP1, while GPS intervention inhibited the expressions of MIF and SPP1. In the animal experiment, GPS intervention treatment alleviated liver injury in rats with hepatic fibrosis and inhibited the expressions of MIF and SPP1, as well as α-SMA and COL1A1 in liver tissue. Conclusion GPS may prevent macrophage-mediated hepatic fibrosis by inhibiting the MIF-SPP1 signaling pathway in hepatic stellate cells.
Hepatic Stellate Cells/metabolism* ; Signal Transduction/drug effects* ; Macrophage Migration-Inhibitory Factors/genetics* ; Liver Cirrhosis/prevention & control* ; Macrophages/drug effects* ; Iridoid Glucosides/pharmacology* ; Humans ; Cell Proliferation/drug effects* ; Animals ; Cell Line ; Collagen Type I/metabolism* ; Collagen Type I, alpha 1 Chain ; Intramolecular Oxidoreductases/genetics* ; Rats ; Transforming Growth Factor beta/pharmacology* ; Actins/metabolism*

As a new strategy for the application of sacubitril/valsartan (LCZ696) in patients with CKD, much evidence showed that it improved the prognosis of patients with CKD. This review summarizes the efficacy and safety of sacubitril/valsartan in physiology, pathology, pharmacology and clinical application by searching Wanfang, CNKI, PubMed and other databases for related articles on the application of sacubitril/valsartan in CKD patients. Although LBQ657, the active product of sacubitril, has a high drug accumulation in patients with moderate, severe renal injury, and ESRD, it is not cleared in hemodialysis, and has very little eliminated in peritoneal dialysis, which does not affect its safety. Compared with angiotensin converting enzyme inhibitor and angiotensin receptor blocker drugs, LCZ696 could increase the blood pressure control rate, improve cardiac function, slow down the decline of glomerular filtration rate, and significantly improve cardiovascular outcomes without more adverse events. Sacubitril/valsartan can be used in all levels of CKD patients complicated with hypertension and/or heart failure, with reliable safety and tolerance.

Objective To investigate the serum microRNA(miR)-125a-5p,miR-127-3p expression and clinical significance in patients with hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC).Meth-ods A total of 90 HBV-associated HCC patients admitted to a hospital from January 2018 to October 2020 were selected as the HBV-associated HCC group.Another 90 healthy subjects from the same period were se-lected as the control group.Serum miR-125a-5p and miR-127-3p expressions were detected by real-time fluo-rescence quantitative polymerase chain reaction.To analyze the relationship between miR-125a-5p and miR-127-3p expression and pathological features of patients with HBV-associated HCC.Patients with HBV-associ-ated HCC were divided into high and low expression groups according to the mean values of serum miR-125a-5p and miR-127-3p expression,and the different survival curves of each groups were plotted by the Kaplan-Meier method.Factors affecting the prognosis of patients with HBV-associated HCC were analyzed by Cox re-gression,and the predictive value of serum miR-125a-5p and miR-127-3p expression on the death of patients with HBV-associated HCC was analyzed by receiver operating characteristic(ROC)curve.Results The rela-tive expression levels of miR-125a-5p and miR-127-3p in HBV-associated HCC group were lower than those in control group,with statistical significance(P＜0.05).There were significant differences in the expression of miR-125a-5p and miR-127-3p in serum of HBV-associated HCC patients with different tumor size,differentia-tion degree,vascular invasion,TNM stage and lymph node metastasis(P＜0.05).Kaplan-Meier survival curve analysis showed that the 3-year overall survival rate(64.58％)of the group with high expression of miR-125a-5p was higher than that of the group with low expression of miR-125a-5p(38.10％).The 3-year overall survival rate of miR-127-3p high expression group(66.00％)was higher than that of miR-127-3p low expres-sion group(35.00％),and the difference was statistically significant(x2=7.770,9.507,P=0.005,0.002).The independent risk factors for death in HBV-associated HCC patients were maximum tumor diameter ≥5 cm,low differentiation,vascular invasion,TNM stage Ⅲ-Ⅳ,and lymph node metastasis,and the independent protective factors were elevated miR-125a-5p and miR-127-3p.ROC curve analysis results showed that the are-a under the curve(AUC)for the combined prediction of serum miR-125a-5p and miR-127-3p expression was 0.907,which was significantly higher than the AUC for the individual prediction of serum miR-125a-5p and miR-127-3p expression(0.790,0.787),with a statistically significant difference(Z=2.691,3.152,P=0.007,0.002).Conclusion The low expression of serum miR-125a-5p and miR-127-3p in HBV-associated HCC pa-tients is related to tumor maximum diameter,differentiation degree,vascular invasion,TNM stage and prog-nosis.The combined expression of serum miR-125a-5p and miR-127-3p has a high predictive value for the prognosis of HBV-associated HCC patients.

Objective To evaluate the prognostic significance of lymph node ratio (LNR) in axillary lymph node positive breast cancer.Methods Eight hundred and three cases axillary lymph node positive breast cancer patients without distant metastasis were systematically treated in the Obstetrics and Gynecology Hospital of Fudan University from 2006 to 2014,at least 10 lymph node removed in each case.Clinicopathological data including 5-year disease-free survival rate (5y-DFSR) and 5-year overall survival rate (5y-OSR) were described.Factors related with prognosis were analyzed by univariate analysis.Prognostic difference was compared among different LNR stage in each axillary lymph node pathological stage(pN).Prognostic significance of pN and LNR was compared by multivariate analysis.Results Mean lymph nodes removed were 15.47±4.70 lymph,and median positive lymph nodes were 4 lymph in 803 cases axillary lymph node positive breast cancer patients.Altogether 159 cases of local recurrence and distant metastasis and 99 cases of breast cancer-related death occurred during median follow-up of 61 months.Five-year DFSR was 77％ and 5y-OSR was 83％.Log-rank univariate analysis showen that pT,pN,LNR,lymphovascular invasion and ER status were related to DFS and OS.Five-year DFSR and OSR for pN1,pN2,pN3 were 89％,68％,59％ and 93％,78％,63％,respectively,whereas 5y-DFSR and 5y-OSR for LNR1,LNR2,LNR3 were 90％,69％,56％ and 94％,80％,57％,respectively.There was statistically significant difference among different LNR in pN1 and pN2 (pN1:DFS:P=0.005,0S:P=0.024;pN2:DFS:P=0.017,0S:P=0.000),but not in pN3,inspite of difference tendency (DFS:P =0.165,OS:P =0.075).In multivariate analysis,when pN or LNR were entered into the Cox regression mode respectively,both were the independent prognostic factors of DFS(P＜0.001) and OS(P＜0.001).When pN and LNR were entered into the Cox hazard regression model at the same time,LNR remained as the independent prognostic factor of DFS and OS (P ＜ 0.001),but pN lost significance (DFS:P =0.461,OS:P=0.162).Conclusion LNR is independent prognostic factor for positive axillary lymph node breast cancer.

Objective To evaluate the clinicopathological characteristics of mucinous breast carcinoma (MBC) and its prognosis.Methods 112 cases of MBC treated in Obstetrics and Gynecology Hospital of Fudan University between Jan 2005 and Dec 2014 were enrolled retrospectively together with 1 157cases of invasive ductal carcinoma (IDC) for comparison.There were 71 cases of pure MBC (PMBC) and 41cases of mixed MBC (MMBC).PMBC and MMBC were compared with each other,and were also compared with IDC respectively.Results PMBC had smaller tumor mass,higher expression rate of hormone receptors (all P＜0.05),lower rate of lymph node metastasis (7.0％ vs.40.6％,x2 =32.663,P ＜0.001) when compared with IDC.The 5 year disease free survival (DFS) and overall survival (OS) of PMBC were both better than those of IDC (DFS:94.6％ ±3.0％ vs.81.3％ ± 1.1％,x2 =7.265,P =0.007;OS:92.4％ ±5.3％ vs.88.5％ ± 1.0％,x2 =4.059,P =0.044).MMBC had relatively larger tumor mass,higher expression rate of hormone receptor,but had no difference in the rate of lymph node metastasis (48.8％ vs.40.6％,x2 =3.417,P =0.332) when compared with IDC.There was no statistically significant difference in 5 yearDFSandOSbetweenMMBCandIDC (DFS:79.1％ ±7.1％ vs.81.3％±1.1％,x2 =0.167,P=0.683;OS:84.5％ ±7.2％ vs.88.5％ ± 1.0％,x2 =0.123,P =0.726).PMBC had relatively smaller tumor mass,lower rate of lymph node metastasis,but had no difference in the expression rate of hormone receptors.The 5 year DFS and OS of MMBC were both better than those of MMBC (DFS:94.6％ ± 3.0％ vs.79.1％±7.1％,x2 =6.772,P =0.009;OS:92.4％ ±5.3％ vs.84.5％ ±7.2％,x2 =6.401,P=0.036).Lymph node status was the only statistically significant prognostic factor of MBC by COX multivariate analysis.Conclusions PMBC has better prognosis than MMBC and IDC owing to its lower rate of lymph node metastasis.MMBC has higher rate of node metastasis than PMBC,hence similar prognosis with IDC.

Objective To evaluate the effect of ultrasound-guided vacuum-assisted minimal invasive resection(Mammotome procedure)of breast lumps through the retromammary space. Methods Seven hundred and eighty-seven patients in Obstetrics and Gynecology Hospital Affiliated to Fudan University from Jan. 2011 to May 2012 were underwent ultrasound-guided Mammotome operation through the retromammary space (retromammary space group,385 cases),or adjacent the lumps,and followed by post-operation visits regularly (Mammotome operation adjacent the lumps group,402 cases). The operation effects were compared between the two groups. Results All cases were followed up for 12 months. The period of Mmmotome operation through the retromam mary space and the rate of resection were(48 ± 6)min and(52 ± 4)min,99. 48%(383 / 385), 99. 25%(399 / 402),perspectively,in group of Mammotome operation through the retromammary space and Mammotome operation adjacent lumpsand. There was no significant difference between the two groups( P> 0. 05). The amount of procedural bleeding,the incidence of ecchymosis,local hematoma and the number of incision in group of Mammotome operation through the retromammary space were(8 ± 3)ml,2. 34%(9 / 385), 0. 52%(2 / 385),(1. 3 ± 0. 6)respectively,which were significantly lower than those in Mammotome operation adjacent the lumps group((14 ± 6)ml,8. 71%(35 / 402),2. 74%(11 / 402),(2. 4 ± 0. 3)respectively). There were statistical difference between two groups( P = 0. 003,P < 0. 001,P = 0. 001,P = 0. 006). The rate of satisfaction in group of Mammotome operation through the retro-mammary space was 98. 70%(380 / 385),which is significantly higher than in group of Mammotome operation adjacent the lumps(89. 30%(359 / 402),P< 0. 01). Conclusion The therapy approach of ultrasound-guided Mammotome operation through the retromammary space has lower hemorrhagic complication,as well as the better effect with special advantages. Therefore it has prospective clinical application.

Objective To summarize and explore the clinical value of Mammotome technology in the diagnosis and treatment of breast neoplasms. Methods Nine hundred and eighty-seven breast neoplasms of 710patients were biopsied and excised with the aid of ultrasound-guided Mammotome system. The malignant neoplasms,according to the histological report,were radically removed during the operation without delay. All patients enrolled into the study were followed up closely on the complcations and satisfaction degree. Results All the operations except one were successful and got the sufficient specimen to perform the pathological examination,the biopsy achievement rate was 99. 8% . Both the sensitivity and specificity of the diagnosis were 100% in 16 breast tumors. Complete resection rate was 99%. The incision length was about 3 mm,showing good cosmetic outcome. Complcations were mild,mainly composed of haematoma and ecchymosis. The patients' general satisfactory rate was 93%. Conclusions This technique can help achieve biopsy of breast neplasm and excision of benign lesions at the same time with cosmetic result Further attention should be paid to reduce the lesion residue and hemorrhagic complications.

Objective To evaluate the effect and clinical value of open surgery combined ultrasound-guided Mammotome in the treatment of multiple breast lumps. Methods Four hundred and forty-four patients in our hospital from Jan. 2006 to Jun. 2008 were divided into 3 groups, who underwent classical open surgery, ultrasound-guided Mammotome operation, or combined therapy respectively and followed by post-operation visits reguarly. The operation effects were compared between the 3 groups. Results Compared with the classical open surgery, combined therapy had no difference in time of procedure and procedural bleeding, but had lower incidence of local skin, better incision condition and higher satisfaction of patients. Compared with ultrasound-guided Mammotome operation, combined therapy took less time in procedure, and in the same time had less procedural bleeding, lower post-operation complication and higher patients satisfaction. Conclusions Combined therapy has high complete removal rate, low post-operation complication as well as cosmetic effect. It has special advantages over the other two kinds of surgery, so it has wide clinical application.

Objective To investigate the effect of advanced glycation end products(AGEs)on expression of vascular endothelial growth factor(VEGF)in rabbit retinal M?ller cells in vitro.Methods We successfully cultured rabbit retinal M?ller cells and made AGEs-BSA as well as its control in vitro.Study with M?ller cells were divided into AGEs-BSA group,AGEs-BSA control group and blank control group.AGEs-BSA group and AGEs-BSA control group were respectively treated with 5 different concentration series of AGEs-BSA and AGEs-BSA control and cultured for 3,6 and 9 days,while blank control group was incubated without any intervention.Then VEGF expression in M?ller cells was observed by immunocytochemistry(ICC).Results Compared with control group,VEGF expression in cultured retinal M?ller cells was significantly enhanced in AGEs-BSA group.And the effects were in the time-and concentration-dependent manners.Conclusions AGEs increases VEGF expression in rabbit retinal M?ller cells in vitro,which indicates that AGEs may promote the progression of diabetic retinopathy(DR)through the induction of VEGF expression.

OBJECTIVE:To observe the clinical efficacy of Yiru tiaojing granules on hyperprolacfinemia(HPRL)of renal deficiency and liver stagnation type.METHODS:HPRL patients were randomized to treatment group(Yiru tiaojing granules)or treatment group(Bromocriptine)for 3 months.Patients' symptoms and sex hormone were recorded.RESULTS:As compared with before treatment,serum level of prolactin(PRL)was significantly reduced(P