放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白...放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白翻译等均有重要调节作用。mTOR异常表达与肿瘤发生及治疗反应密切相关。肿瘤的放疗敏感性与"4R"效应有关。mTOR抑制剂可通过影响细胞周期进展、DNA损伤修复及抗血管形成等多种途径发挥放疗增敏作用。初期研究证实依维莫司具有放疗增敏作用并且毒性可耐受。应用mTOR抑制剂后不同细胞及个体反应不同,可能与基因表达状态有关,需进一步研究证实。展开更多
AIM: To investigate whether the simultaneous treatment with human growth hormone(h GH) abolishes the negative effects of everolimus on anastomotic healing.METHODS: Forty-eight male Sprague-Dawley-rats were randomized ...AIM: To investigate whether the simultaneous treatment with human growth hormone(h GH) abolishes the negative effects of everolimus on anastomotic healing.METHODS: Forty-eight male Sprague-Dawley-rats were randomized to three groups of 16 animals each(Ⅰ: vehicle; Ⅱ: everolimus 3 mg/kg po; Ⅲ: everolimus 3 mg/kg po + h GH 2.5 mg/kg sc). Animals were pretreated with h GH and/or everolimus daily for seven days. Then a standard anastomosis was created in the descending colon and treatment was continued for another seven days. The anastomosis was resected in toto and the bursting pressure was assessed as a mechanical parameter of intestinal healing. Moreover, biochemical(Hydroxyproline, PCNA, MPO, MMP-2 and MMP-9) and histological(cell density, angiogenesis, amount of granulation tissue) parameters of intestinal healing were assessed.RESULTS: Anastomotic bursting pressure was significantly reduced by everolimus and a simultaneous treatment with h GH resulted in considerably higher values(Ⅰ: 134 ± 19 mm Hg, Ⅱ: 85 ± 25 mm Hg, Ⅲ: 114 ± 25 mm Hg; P < 0.05,Ⅰvs Ⅱ; P = 0.09,Ⅰvs Ⅲ and Ⅱ vs Ⅲ) Hydroxyproline concentration was significantly increased by h GH compared to everolimus alone(Ⅰ: 14.9 ± 2.5 μg/mg, Ⅱ: 8.9 ± 3.6 μg/mg, Ⅲ: 11.9 ± 2.8 μg/mg; P < 0.05,?Ⅰvs Ⅱ/Ⅲ and Ⅱ vs Ⅲ). The number of MPO-positive cells was reduced significantly by h GHcompared to everolimus alone(Ⅰ: 10 ± 1 n/mm^2, Ⅱ: 15 ± 3 n/mm^2, Ⅲ: 9 ± 2 n/mm^2; P < 0.05,Ⅰvs Ⅱ and Ⅱ vs Ⅲ), while the number of PCNA-positive cells were increased by h GH(Ⅰ: 28 ± 3 /mm^2, Ⅱ: 12 ± 3 /mm^2, Ⅲ: 26 ± 12 /mm^2; P < 0.05,?Ⅰ?vs Ⅱ and Ⅱ vs Ⅲ). Corresponding to these biochemical findings, HEhistology revealed significantly increased amount of granulation tissue in h GH-treated animals.CONCLUSION: Inhibition of intestinal wound healing by everolimus is partially neutralized by simultaeous treatment with h GH. Both inflammation as well as collagen deposition is influenced by h GH.展开更多
De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two ...De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma(HCC) recurrence have been reported with the use of m TOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs m TOR-inhibitorfree immunosuppression is more efficacious in reducing HCC recurrence.展开更多
Adhesions are the most frequent complication of abdominopelvic surgery,yet the extent of the problem,and its serious consequences,has not been adequately recognized.Adhesions evolved as a life-saving mecha-nism to lim...Adhesions are the most frequent complication of abdominopelvic surgery,yet the extent of the problem,and its serious consequences,has not been adequately recognized.Adhesions evolved as a life-saving mecha-nism to limit the spread of intraperitoneal inflammatory conditions.Three different pathophysiological mechanisms can independently trigger adhesion formation.Mesothelial cell injury and loss during operations,tissue hypoxia and inflammation each promotes adhesion formation separately,and potentiate the effect of each other.Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation.This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions.It explores the prom-ising role of combinatorial gene therapy and vector modif ications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field.展开更多
AIM:To compare efficacy of proton pump inhibitors(PPIs)with H2-receptor antagonists(H2RAs)plus prokinetics(Proks)for dysmotility-like symptoms in functional dyspepsia(FD).METHODS:Subjects were randomized to receive op...AIM:To compare efficacy of proton pump inhibitors(PPIs)with H2-receptor antagonists(H2RAs)plus prokinetics(Proks)for dysmotility-like symptoms in functional dyspepsia(FD).METHODS:Subjects were randomized to receive openlabel treatment with either rabeprazole 10 mg od(n= 57)or famotidine 10 mg bid plus mosapride 5 mg tid(n=57)for 4 wk.The primary efficacy endpoint was change(%)from baseline in total dysmotility-like dyspepsia symptom score.The secondary efficacy endpoint was patient satisfaction with treatment.RESULTS:The improvement in dysmotility-like dyspep-sia symptom score on day 28 was significantly greater in the rabeprazole group(22.5%±29.2%of baseline) than the famotidine+mosapride group(53.2%± 58.6%of baseline,P<0.0001).The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status.Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine+mosapride group(87.7%vs 59.6%,P= 0.0012).Rabeprazole therapy was the only significant predictor of treatment response(P<0.0001),defined as a total symptom score improvement≥50%.CONCLUSION:PPI monotherapy improves dysmotility-like symptoms significantly better than H2RAs plus Proks,and should be the treatment of first choice for Japanese FD.展开更多
【目的】明确TOR(Target of Rapamycin)信号通路抑制剂雷帕霉素对荔枝霜疫霉生长发育、致病性及自噬的影响。【方法】采用不同浓度的TOR抑制剂雷帕霉素处理荔枝霜疫霉菌,观察不同浓度雷帕霉素对荔枝霜疫霉的菌丝生长及形态、孢子囊产生...【目的】明确TOR(Target of Rapamycin)信号通路抑制剂雷帕霉素对荔枝霜疫霉生长发育、致病性及自噬的影响。【方法】采用不同浓度的TOR抑制剂雷帕霉素处理荔枝霜疫霉菌,观察不同浓度雷帕霉素对荔枝霜疫霉的菌丝生长及形态、孢子囊产生数量、游动孢子释放和致病性的影响,并通过丹酰戊二胺(MDC)染色观察细胞自噬。【结果】雷帕霉素处理后,荔枝霜疫霉的菌丝生长明显受到抑制,半最大效应浓度(EC 50)值为29.18 ng·mL^(−1),随着雷帕霉素浓度的增加,菌丝生长抑制不同程度增加;当雷帕霉素深度为25.0 ng·mL^(−1)时,菌落生长抑菌率为45.3%,孢子囊产生数量为8.0×10^(4)个·mL^(−1),仅为对照组的27.9%;雷帕霉素处理能促进游动孢子的释放;同时严重影响荔枝霜疫霉菌的致病性。通过自噬体观察表明,雷帕霉素处理后荔枝霜疫霉菌丝中自噬体的数量显著增加,促进荔枝霜疫霉的细胞自噬。【结论】TOR抑制剂雷帕霉素通过调控荔枝霜疫霉的细胞自噬,从而影响病菌的生长发育及致病性,研究结果为荔枝霜疫霉的致病机制提供科学依据。展开更多
AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were inject...AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear transloca-tion of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.展开更多
文摘放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白翻译等均有重要调节作用。mTOR异常表达与肿瘤发生及治疗反应密切相关。肿瘤的放疗敏感性与"4R"效应有关。mTOR抑制剂可通过影响细胞周期进展、DNA损伤修复及抗血管形成等多种途径发挥放疗增敏作用。初期研究证实依维莫司具有放疗增敏作用并且毒性可耐受。应用mTOR抑制剂后不同细胞及个体反应不同,可能与基因表达状态有关,需进一步研究证实。
文摘AIM: To investigate whether the simultaneous treatment with human growth hormone(h GH) abolishes the negative effects of everolimus on anastomotic healing.METHODS: Forty-eight male Sprague-Dawley-rats were randomized to three groups of 16 animals each(Ⅰ: vehicle; Ⅱ: everolimus 3 mg/kg po; Ⅲ: everolimus 3 mg/kg po + h GH 2.5 mg/kg sc). Animals were pretreated with h GH and/or everolimus daily for seven days. Then a standard anastomosis was created in the descending colon and treatment was continued for another seven days. The anastomosis was resected in toto and the bursting pressure was assessed as a mechanical parameter of intestinal healing. Moreover, biochemical(Hydroxyproline, PCNA, MPO, MMP-2 and MMP-9) and histological(cell density, angiogenesis, amount of granulation tissue) parameters of intestinal healing were assessed.RESULTS: Anastomotic bursting pressure was significantly reduced by everolimus and a simultaneous treatment with h GH resulted in considerably higher values(Ⅰ: 134 ± 19 mm Hg, Ⅱ: 85 ± 25 mm Hg, Ⅲ: 114 ± 25 mm Hg; P < 0.05,Ⅰvs Ⅱ; P = 0.09,Ⅰvs Ⅲ and Ⅱ vs Ⅲ) Hydroxyproline concentration was significantly increased by h GH compared to everolimus alone(Ⅰ: 14.9 ± 2.5 μg/mg, Ⅱ: 8.9 ± 3.6 μg/mg, Ⅲ: 11.9 ± 2.8 μg/mg; P < 0.05,?Ⅰvs Ⅱ/Ⅲ and Ⅱ vs Ⅲ). The number of MPO-positive cells was reduced significantly by h GHcompared to everolimus alone(Ⅰ: 10 ± 1 n/mm^2, Ⅱ: 15 ± 3 n/mm^2, Ⅲ: 9 ± 2 n/mm^2; P < 0.05,Ⅰvs Ⅱ and Ⅱ vs Ⅲ), while the number of PCNA-positive cells were increased by h GH(Ⅰ: 28 ± 3 /mm^2, Ⅱ: 12 ± 3 /mm^2, Ⅲ: 26 ± 12 /mm^2; P < 0.05,?Ⅰ?vs Ⅱ and Ⅱ vs Ⅲ). Corresponding to these biochemical findings, HEhistology revealed significantly increased amount of granulation tissue in h GH-treated animals.CONCLUSION: Inhibition of intestinal wound healing by everolimus is partially neutralized by simultaeous treatment with h GH. Both inflammation as well as collagen deposition is influenced by h GH.
文摘De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma(HCC) recurrence have been reported with the use of m TOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs m TOR-inhibitorfree immunosuppression is more efficacious in reducing HCC recurrence.
基金Supported by The United States-Egypt Science and Technology Joint Fund in cooperation with United States Department of Agriculturethe Egyptian Science and Technology Development Fund under Project 739
文摘Adhesions are the most frequent complication of abdominopelvic surgery,yet the extent of the problem,and its serious consequences,has not been adequately recognized.Adhesions evolved as a life-saving mecha-nism to limit the spread of intraperitoneal inflammatory conditions.Three different pathophysiological mechanisms can independently trigger adhesion formation.Mesothelial cell injury and loss during operations,tissue hypoxia and inflammation each promotes adhesion formation separately,and potentiate the effect of each other.Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation.This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions.It explores the prom-ising role of combinatorial gene therapy and vector modif ications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field.
文摘AIM:To compare efficacy of proton pump inhibitors(PPIs)with H2-receptor antagonists(H2RAs)plus prokinetics(Proks)for dysmotility-like symptoms in functional dyspepsia(FD).METHODS:Subjects were randomized to receive openlabel treatment with either rabeprazole 10 mg od(n= 57)or famotidine 10 mg bid plus mosapride 5 mg tid(n=57)for 4 wk.The primary efficacy endpoint was change(%)from baseline in total dysmotility-like dyspepsia symptom score.The secondary efficacy endpoint was patient satisfaction with treatment.RESULTS:The improvement in dysmotility-like dyspep-sia symptom score on day 28 was significantly greater in the rabeprazole group(22.5%±29.2%of baseline) than the famotidine+mosapride group(53.2%± 58.6%of baseline,P<0.0001).The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status.Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine+mosapride group(87.7%vs 59.6%,P= 0.0012).Rabeprazole therapy was the only significant predictor of treatment response(P<0.0001),defined as a total symptom score improvement≥50%.CONCLUSION:PPI monotherapy improves dysmotility-like symptoms significantly better than H2RAs plus Proks,and should be the treatment of first choice for Japanese FD.
基金Supported by Shanghai Municipal Health Bureau Youth Grant, No. 2008Y032
文摘AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear transloca-tion of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.
