Objective To compare the efficacy and adherence of rivaroxaban versus low-molecular-weight heparin for prophylactic anticoagulation in cancer patients with venous thromboembolism(VTE).Methods A total of 120 intermediate-to-high VTE risk patients with malignant tumors admitted to Depart-ment of Hematology and Oncology,West China Longquan Hospital of Sichuan University between September 2021 and December 2022,were randomly assigned to the rivaroxaban group(n=60)and the low-molecular-weight heparin group(n=60)using the random number table.The rivaroxaban group received oral Rivaroxa-ban,while the low-molecular-weight heparin group received subcutaneous injections of low-molecular-weight heparin sodium for prophylactic anticoagulation.All patients were followed up for 180 days.The primary end-point was medication adherence.The secondary endpoints included the incidence of VTE,bleeding events,and changes in coagulation parameters.Results The rate of good medication adherence was significantly higher in the rivaroxaban group than in the low-molecular-weight heparin group(95.00％vs.88.33％,P＜0.05).However,there were no statistically significant differences in the incidence of VTE or overall bleeding events between the two groups(P＜0.05).Following treatment,parameters including fibrinogen,prothrombin time(PT),and D-dimer levels showed significant improvement from baseline in both groups.Compared to the low-molecular-weight heparin group,the Rivaroxaban group demonstrated significantly higher fibrinogen levels,shorter PT,and lower D-dimer levels(P＜0.05).Stepwise logistic regression analysis identified the post-treatment platelet(PLT)count as a significant factor influencing bleeding events during prophylactic antico-agulation(P＜0.05).Khorana score≥3(high risk)was identified as a risk factor for bleeding events(P＜0.05).The incidence of clinically relevant non-major bleeding(CRNMB)was higher in the rivaroxaban group[11.67％(7/60)]compared to the low-molecular-weight heparin group[8.33％(5/60)],although the differ-ence was not statistically significant(P＜0.05).Kaplan-Meier curve analysis revealed no significant difference in the cumulative incidence of bleeding-free events between the two groups(P＜0.05).Conclusion Oral ri-varoxaban and subcutaneous low-molecular-weight heparin demonstrate comparable efficacy and safety for VTE prevention in cancer patients,but rivaroxaban significantly improves patient's adherence.

Objective:To observe the role of complement C3 in the process of renal interstitial fibrosis.Methods:Renal interstitial fibrosis model was established by unilateral ureteral obstruction (UUO) in male C3-deficient (C3KO) mice and age-matched C57BL/6 wild type (WT) mice (8-12 weeks of age). Mice were randomly divided into 4 groups, including sham operation in WT group (WTcontrol) ( n=6), UUO operation in WT group (WTuuo) ( n=6), sham operation in C3-deficient group (C3KOcontrol) ( n=6), and UUO operation in C3-deficient group (C3KOuuo) ( n=6). Tubular interstitial fibrosis was observed by both HE staining and Masson staining. The expression of C3, trypsin (tryptase), angiotensinⅡ (AngⅡ), transforming growth factor β1 (TGF-β1), and matrix metalloproteinase-9 (MMP-9) was detected by immunohistochemical staining. Chymase level were assessed by immunofluorescence staining. The levels of AngⅡ and C3 cleavage fragments C3a and MMP-9 were determined by enzyme-linked immunosorbent assay. The change in renin mRNA was determined by real-time PCR. The changes of chymase, renin, and TGF-β1 were detected by Western blotting. Results:Compared with the WTcontrol group mice, the WTuuo group mice showed significant renal tubular injury, renal interstitial fibrosis, increased infiltration of mast cells, and significantly increased expression of C3, C3a, chymase, renin, AngⅡ, TGF-β1, and MMP-9 in the renal tissue (all P<0.05). Compared with the WTuuo group mice, the renal tubular injury and renal interstitial fibrosis in the C3KOuuo group mice were significantly reduced, and C3 and C3a were not detected in renal tissue. Mast cells infiltration was reduced, and the expression of chymase, renin, AngⅡ, TGF-β1, and MMP-9 was weakened (all P<0.05). Conclusion:C3/C3a can participate in the recruitment and activation of mast cells to release chymase in kidney interstitial fibrosis, and promote the expression of renin, AngⅡ, TGF-β1, MMP 9 and other substances, thus aggravating kidney injury.

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs prolifer-ation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Objective To investigate the effect of down-regulating adenosine deaminase acting on RNA-1(AD AR1)on the radiosensitivity of lung adenocarcinoma cells.Methods Lentiviral transfection was used to establish an ADAR1 knockdown cell line based on A549 cells.Then the cells were divided into negative control(shNC)and ADAR1 knockdown(shADAR1)groups,which were followed by a single-dose irradiation of 0 Gy and 6 Gy X-rays.Western blotting and RT-PCR were utilized to detect the expression of AD AR1 at protein and mRNA levels,respectively.CCK-8 assay,wound healing assay and Transwell migration assay were applied to measure cell proliferation and migration abilities.Meanwhile,clone formation assay was performed to detect the effect of down-regulating ADAR1 on the radiosensitivity of A549 cells.Flow cytometry and Western blotting were conducted to detect the expression levels of apoptosis and apoptosis-related proteins Bax and Bcl-2.Immunofluorescence assay and Western blotting were used to detect the expression level of γ-H2AX.Comet assay was performed to detect the level of cellular DNA damage.Twelve female nude mice(4～6 weeks old,weighing 16～18 g)were divided into shNC group,shADAR1 group,shNC+ionizing radiation(IR)group and shADAR1+IR group,with 3 mice in each group.The growth of tumor of different groups was observed with subcutaneous tumorigenesis assay.Results Western blotting and RT-qPCR showed that the protein and mRNA expression of ADAR1 were significantly reduced in A549 shADAR1 cells(P＜0.05).CCK-8 assay,wound healing assay and Transwell migration assay indicated that down-regulation of ADAR 1 inhibited the proliferation and migration abilities of A549 cells,and this inhibition trend became more obvious(P＜0.01)after IR.Cell clone formation assay showed that the clone formation rate of both groups was decreased,with the increase of radiation dose.But the number of formed clones was lower in the shADAR1 group than the shNC group.Flow cytometry and Western blotting displayed that down-regulation of AD AR1 increased the apoptotic rate and Bax expression in A549 cells(P＜0.01)and decreased Bcl-2 expression(P＜0.05),and the apoptotic rate and Bax protein level were further increased in A549 shADAR1 cells after IR(P＜0.01),and the Bcl-2 protein level was further decreased(P＜0.01).The number of γ-H2AX foci and protein level in A549 shADAR1 cells were significantly increased after IR(P＜0.05),and the results of comet assay showed that the DNA damage was more obvious in A549 shADAR1 cells after IR(P＜0.01).Subcutaneous tumorigenesis assay in nude mice showed that the growth of subcutaneous tumour of A549 shADAR1 cells was significantly inhibited after IR(P＜0.01).Conclusion Down-regulation of ADAR1 significantly inhibits the proliferation and migration of A549 cells after IR and promotes apoptosis and DNA damage,and thereby increases the radiosensitivity of lung adenocarcinoma cells.

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 observe the role of complement C3 in the process of renal interstitial fibrosis.Methods:Renal interstitial fibrosis model was established by unilateral ureteral obstruction (UUO) in male C3-deficient (C3KO) mice and age-matched C57BL/6 wild type (WT) mice (8-12 weeks of age). Mice were randomly divided into 4 groups, including sham operation in WT group (WTcontrol) ( n=6), UUO operation in WT group (WTuuo) ( n=6), sham operation in C3-deficient group (C3KOcontrol) ( n=6), and UUO operation in C3-deficient group (C3KOuuo) ( n=6). Tubular interstitial fibrosis was observed by both HE staining and Masson staining. The expression of C3, trypsin (tryptase), angiotensinⅡ (AngⅡ), transforming growth factor β1 (TGF-β1), and matrix metalloproteinase-9 (MMP-9) was detected by immunohistochemical staining. Chymase level were assessed by immunofluorescence staining. The levels of AngⅡ and C3 cleavage fragments C3a and MMP-9 were determined by enzyme-linked immunosorbent assay. The change in renin mRNA was determined by real-time PCR. The changes of chymase, renin, and TGF-β1 were detected by Western blotting. Results:Compared with the WTcontrol group mice, the WTuuo group mice showed significant renal tubular injury, renal interstitial fibrosis, increased infiltration of mast cells, and significantly increased expression of C3, C3a, chymase, renin, AngⅡ, TGF-β1, and MMP-9 in the renal tissue (all P<0.05). Compared with the WTuuo group mice, the renal tubular injury and renal interstitial fibrosis in the C3KOuuo group mice were significantly reduced, and C3 and C3a were not detected in renal tissue. Mast cells infiltration was reduced, and the expression of chymase, renin, AngⅡ, TGF-β1, and MMP-9 was weakened (all P<0.05). Conclusion:C3/C3a can participate in the recruitment and activation of mast cells to release chymase in kidney interstitial fibrosis, and promote the expression of renin, AngⅡ, TGF-β1, MMP 9 and other substances, thus aggravating kidney injury.

Purpose: Oligometastatic non–small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome. However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis. Materials and Methods: We performed next-generation sequencing to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity. Results: We found ERBB2, ALK, MLL4, PIK3CB, and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden of oligometastasis was 5.00 mutations/Mb, which was significantly associated with smoking, DNA damage repair genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation. Conclusion Our results shall help redefine oligometastasis beyond simple lesion enumeration that will ultimately improve the selection of patients with real oligometastatic state and optimize personalized cancer therapy for oligometastatic NSCLC.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

The occurrence of cholestatic liver injury is accompanied by the alterations of hepatocyte polarization and bile acid homeostasis. Located in epithelial cells, tight junctions(TJs)are a special barrier structure which are important in maintaining permeability and bile acid homeostasis. Based on the fully analysis and discussion of TJs, the latest therapeutic drugs for cholestasis were summaried, which may provide new perspectives and potential therapeutic agents for the treatment of cholestatic liver injury.

Objective To analyze the safety and efficacy of laparoscopic radical resection of colorectal cancer for elderly patients over 70 years old. Methods From January 2014 to January 2017,a retrospective analysis of the patients with radical surgery for colorectal cancer in Department of General Surgery,Beijing Anzhen Hospital,Capital Medical University was performed. According to the patient′s age, the patients were divided into ≥70 years old group (68 cases) and＜70 years old group (84 cases). The preoperative clinical data of the two groups were analyzed. The surgeons strictly followed the standard lymph node cleaning and the principle of no tumor for colorectal cancer radical operation. The surgical conditions, pathology,short-term efficacy and the follow-up conditions of the two groups were compared. Statistical analysis was performed using SPSS 20. 0. The normal distribution of the data was expressed as Mean±SD,and the t-test was used for comparison between the group. The count data was compared using the χ2 test or the Fisher exact probability method. Results The operation was successfully completed in both groups. In the group of≥70 years old,2 cases were converted to open due to extensive adhesion of the abdominal cavity,no perioperative death. Compared with the＜70 years old group,≥70 years old group had more hypertension and coronary heart disease, respectively ( 38. 2%( 26/68 ) vs. 14. 3%( 12/84 )), and the difference was statistically significant ( P＜0. 05 ) . There was no significant difference in intraoperative blood loss and operation time between the two groups (P＞0. 05) . There was statistically significant difference in incidence of postoperative cardiovascular events between the groups (26. 4%(18/68) vs. 7. 14%(6/84)χ2＝ 6. 428, P＝0. 010) . However,there were no significant differences between the two groups in implications,rate of death and the time stayed in hospital. (P＞0. 05). Conclusion Laparoscopic radical resection for colorectal cancer patients over 70 years old is safe and feasible with strict indications and attention to perioperative management.