AIM: To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. METHODS: Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg)...AIM: To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. METHODS: Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. RESULTS: At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P < 0.001). Specifically, the F4 group had a significantly higher elastic modulus than the F3, F2, and F0 groups (P = 0.002, P = 0.003, and P = 0.006, respectively), and the F3 group also had a significantly higher modulus than the control F0 group (P = 0.039). LSM was negatively associated with plasma MEGX concentrations at 30 min (r = -0.642; P = 0.013) and 60 min (r = -0.651; P = 0.012), time to 1/2 of the maximum concentration (r = -0.538; P = 0.047), and the area under the curve (r = -0.636; P = 0.014). Multiple comparisons showed identical differences in these three measures: significantly lower with F4 (P = 0.037) and F3 (P = 0.032) as compared to F0 and significantly lower with F4 as compared to F2 (P = 0.032). CONCLUSION: SWE LSM shows a good correlation with histologic fibrosis grading and pharmacologic quantitative liver function reserve in experimental severe fibrosis and cirrhosis.展开更多
AIM: To explore the feasibility of non-invasive quantitative estimation of portal venous pressure by contrast-enhanced ultrasound(CEUS) in a canine model.METHODS: Liver fibrosis was established in adult canines(Beagle...AIM: To explore the feasibility of non-invasive quantitative estimation of portal venous pressure by contrast-enhanced ultrasound(CEUS) in a canine model.METHODS: Liver fibrosis was established in adult canines(Beagles; n = 14) by subcutaneous injection of carbon tetrachloride(CCl4). CEUS parameters, including the area under the time-intensity curve and intensity at portal/arterial phases(Qp/Qa and Ip/Ia, respectively), were used to quantitatively assess the blood flow ratio of the portal vein/hepatic artery at multiple time points. The free portal venous pressures(FPP) were measured by a multi-channel baroreceptor using a percutaneous approach at baseline and 8, 16, and 24 wk after CCl4 injections in each canine. Liver biopsies were obtained at the end of 8, 16, and 24 wk from each animal, and the stage of the fibrosis was assessed according to the Metavir scoring system. A Pearson correlation test was performed to compare the FPP with Q p/Q a and I p/I a.RESULTS: Pathologic examination of 42 biopsies from the 14 canines at weeks 8, 16, and 24 revealed that liver fibrosis was induced by CCl4 and represented various stages of liver fibrosis, including F0(n = 3), F1(n = 12), F2(n = 14), F3(n = 11), and F4(n = 2). There were significant differences in the measurements of Qp/Qa(19.85 ± 3.30 vs 10.43 ± 1.21, 9.63 ± 1.03, and 8.77 ± 0.96) and Ip/Ia(1.77 ± 0.37 vs 1.03 ± 0.12, 0.83 ± 0.10, and 0.69 ± 0.13) between control and canine fibrosis at 8, 16, and 24 wk, respectively(all P < 0.001). There were statistically significant negative correlations between FPP and Q p/Q a(r =-0.707, P < 0.001), and between FPP and Ip/Ia(r =-0.759, P < 0.001) in the canine fibrosis model. Prediction of elevated FPP based on Q p/Q a and I p/I a was highly sensitive, as assessed by the area under the receiveroperating curve(0.866 and 0.895, respectively).CONCLUSION: C E U S i s a p o t e n t i a l m e t h o d t o accurately, but non-invasively, estimate portal venous pressure through measurement of Qp/Qa and Ip/Ia parameters.展开更多
In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited b...In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.展开更多
Investment in agricultural capital construction is an important factor in improving China's agricultural productivity and international competitiveness. In recent years,the attention to the investment in agricultu...Investment in agricultural capital construction is an important factor in improving China's agricultural productivity and international competitiveness. In recent years,the attention to the investment in agricultural capital construction has been lifted to a strategic height. However,there is still little research on the investment in agricultural capital construction. From the perspective of investment of different ministries and commissions,this paper systematically analyzed current situations,problems,and came up with recommendations for the investment in the agricultural capital construction. According to the results,( i) from 1983 to the present,China's investment in agricultural capital construction experienced three stages. Especially after 2010,the scale of investment in agricultural capital construction was huge,and it showed a rapid increasing trend;( ii) the investment in agricultural capital construction is characterized by " multi-sector investment,different departments having different investment priorities and investment scale in different periods";( iii) some investment projects are overlapping between departments,local areas are weak in providing support funds,project construction standard is single,and there are problems of attaching importance to the application,belittling the management,stressing the construction,belittling the maintenance,and serious brain drain;( iv) different departments have accumulated certain experience in long-term exploration. For example,they pay more attention to the refinement and differentiation of projects,focus on the development of targeted poverty alleviation,pay more attention to the " quality" of investment,and pay more attention to the transformation of agricultural production methods. Based on current situations and problems,it came up with recommendations including promoting the integration of funds for investment and project integration,strengthening the personnel cultivation,ensuring simultaneous construction and management of projects,stressing the maintenance after project construction,exploring new modes for project design,management,investment,and financing,and enhancing the support for special investment projects.展开更多
Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)wi...Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.展开更多
基金Supported by National Natural Science Foundation of ChinaNo.81401425
文摘AIM: To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. METHODS: Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. RESULTS: At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P < 0.001). Specifically, the F4 group had a significantly higher elastic modulus than the F3, F2, and F0 groups (P = 0.002, P = 0.003, and P = 0.006, respectively), and the F3 group also had a significantly higher modulus than the control F0 group (P = 0.039). LSM was negatively associated with plasma MEGX concentrations at 30 min (r = -0.642; P = 0.013) and 60 min (r = -0.651; P = 0.012), time to 1/2 of the maximum concentration (r = -0.538; P = 0.047), and the area under the curve (r = -0.636; P = 0.014). Multiple comparisons showed identical differences in these three measures: significantly lower with F4 (P = 0.037) and F3 (P = 0.032) as compared to F0 and significantly lower with F4 as compared to F2 (P = 0.032). CONCLUSION: SWE LSM shows a good correlation with histologic fibrosis grading and pharmacologic quantitative liver function reserve in experimental severe fibrosis and cirrhosis.
文摘AIM: To explore the feasibility of non-invasive quantitative estimation of portal venous pressure by contrast-enhanced ultrasound(CEUS) in a canine model.METHODS: Liver fibrosis was established in adult canines(Beagles; n = 14) by subcutaneous injection of carbon tetrachloride(CCl4). CEUS parameters, including the area under the time-intensity curve and intensity at portal/arterial phases(Qp/Qa and Ip/Ia, respectively), were used to quantitatively assess the blood flow ratio of the portal vein/hepatic artery at multiple time points. The free portal venous pressures(FPP) were measured by a multi-channel baroreceptor using a percutaneous approach at baseline and 8, 16, and 24 wk after CCl4 injections in each canine. Liver biopsies were obtained at the end of 8, 16, and 24 wk from each animal, and the stage of the fibrosis was assessed according to the Metavir scoring system. A Pearson correlation test was performed to compare the FPP with Q p/Q a and I p/I a.RESULTS: Pathologic examination of 42 biopsies from the 14 canines at weeks 8, 16, and 24 revealed that liver fibrosis was induced by CCl4 and represented various stages of liver fibrosis, including F0(n = 3), F1(n = 12), F2(n = 14), F3(n = 11), and F4(n = 2). There were significant differences in the measurements of Qp/Qa(19.85 ± 3.30 vs 10.43 ± 1.21, 9.63 ± 1.03, and 8.77 ± 0.96) and Ip/Ia(1.77 ± 0.37 vs 1.03 ± 0.12, 0.83 ± 0.10, and 0.69 ± 0.13) between control and canine fibrosis at 8, 16, and 24 wk, respectively(all P < 0.001). There were statistically significant negative correlations between FPP and Q p/Q a(r =-0.707, P < 0.001), and between FPP and Ip/Ia(r =-0.759, P < 0.001) in the canine fibrosis model. Prediction of elevated FPP based on Q p/Q a and I p/I a was highly sensitive, as assessed by the area under the receiveroperating curve(0.866 and 0.895, respectively).CONCLUSION: C E U S i s a p o t e n t i a l m e t h o d t o accurately, but non-invasively, estimate portal venous pressure through measurement of Qp/Qa and Ip/Ia parameters.
基金supported by National Natural Science Foundation of China(Nos.81690264 and 81973259)the Open Project from Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education/Beijing.
文摘In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.
文摘Investment in agricultural capital construction is an important factor in improving China's agricultural productivity and international competitiveness. In recent years,the attention to the investment in agricultural capital construction has been lifted to a strategic height. However,there is still little research on the investment in agricultural capital construction. From the perspective of investment of different ministries and commissions,this paper systematically analyzed current situations,problems,and came up with recommendations for the investment in the agricultural capital construction. According to the results,( i) from 1983 to the present,China's investment in agricultural capital construction experienced three stages. Especially after 2010,the scale of investment in agricultural capital construction was huge,and it showed a rapid increasing trend;( ii) the investment in agricultural capital construction is characterized by " multi-sector investment,different departments having different investment priorities and investment scale in different periods";( iii) some investment projects are overlapping between departments,local areas are weak in providing support funds,project construction standard is single,and there are problems of attaching importance to the application,belittling the management,stressing the construction,belittling the maintenance,and serious brain drain;( iv) different departments have accumulated certain experience in long-term exploration. For example,they pay more attention to the refinement and differentiation of projects,focus on the development of targeted poverty alleviation,pay more attention to the " quality" of investment,and pay more attention to the transformation of agricultural production methods. Based on current situations and problems,it came up with recommendations including promoting the integration of funds for investment and project integration,strengthening the personnel cultivation,ensuring simultaneous construction and management of projects,stressing the maintenance after project construction,exploring new modes for project design,management,investment,and financing,and enhancing the support for special investment projects.
基金financial support from the Basic Research Cooperation Project of Beijing,Tianjin,Hebei from the Natural Science Foundation of Beijing(No.J200018),Tianjin(No.20JCZXJC00070),and Hebei(No.H2020206649)Beijing Natural Science Foundation(No.7214281)the projects of National Natural Science Foundation of China(No.81973259)。
文摘Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.
