BACKGROUND Mammalian target of rapamycin(mTOR)inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma(HCC).However,their role in established post-tra...BACKGROUND Mammalian target of rapamycin(mTOR)inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma(HCC).However,their role in established post-transplant HCC recurrence is uncertain.AIM To investigate whether mTOR inhibitor offers a survival benefit in posttransplant HCC recurrence.METHODS A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed.They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression.The primary endpoint was post-recurrence survival.RESULTS Seventy-nine(55%)patients received an mTOR inhibitor-based immunosuppressive regime,while 64(45%)patients did not.The mTOR inhibitor group had a lower number of recurrent tumours(2 vs 5,P=0.02)and received more active treatments including radiotherapy(39 vs 22%,P=0.03)and targeted therapy(59 vs 23%,P<0.001).The median post-recurrence survival was 21.0±4.1 mo in the mTOR inhibitor group and 11.2±2.5 mo in the control group.Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival(P=0.04,OR=0.482,95%CI:0.241-0.966).The number of recurrent tumours and use of other treatment modalities did not affect survival.No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor.CONCLUSION mTOR inhibitors prolonged survival after post-transplant HCC recurrence.展开更多
Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reporte...Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reported as altered in neuroendocrine tumors(NETs). m TOR inhibitors used in clinical practice are derived from rapamycin,an anti-cancer agent also used as an immunosuppressor after organ transplantation. Everolimus and temsirolimus are the two rapamycin-derived m TOR inhibitors used in NETs. Notably everolimus has been approved in advanced progressive well/moderatelydifferentiated pancreatic NETs(p NETs). It inhibits specifically the m TORC1 subunit of m TOR,not interacting with m TORC2. Although everolimus produced a significant prolongation of progression-free survival a number of patients with p NETs do not benefit from the drug due to early or late progression. Two supposed mechanisms of resistance to m TOR inhibitors are Akt and PI3 K activation,by means of m TORC2 and insulin growth factor(IGF)- IGF receptor signaling,respectively. BEZ235 is a multi-targeted inhibitor binding to PI3 K,m TORC1 and m TORC2,therefore potentially turning off all the supposed molecular targets of resistance to everolimus. The two clinical trials designed in p NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was also halted. Tolerability of this drug was challenging and conditioned the feasibility of therapy. The BEZ experience is an example of the huge difference between the preclinical and clinical setting and prompts us to pay more attention to the phase Ⅰ step of clinical development and the design of phase Ⅱ clinical trials.展开更多
AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin(m TOR) inhibitors with or without calcineurin inhibitors(C...AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin(m TOR) inhibitors with or without calcineurin inhibitors(CNIs) in renal transplant recipients.METHODS We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, m TOR inhibitors as an alternative to CNI within six months of renal transplant by searching the Pub Med, EMBASE, Cochrane, Crossref, and Scopus using Me SH terms. RESULTS Six articles of early withdrawal of CNI and introduction of m TOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate(GFR) and serum creatinine were significantly better in m TOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in m TOR-inhibitor group. CONCLUSION The evidence reviewed in this meta-analysis suggests that early introduction m TOR-inhibitors substantial CNI minimization. The m TOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.展开更多
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is ...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.展开更多
Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Re...Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Recognition of the molecular and cellular pathways that induce IBD is an emerging subject to develop targeted therapies.Mammalian target of rapamycin(mTOR)is one the most common receptors of many inflammatory pathways,including that of IBD.To this end,we intend to overview the mTOR inhibitors for their possible efficacy in present and future approaches to treatment of IBD.展开更多
多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸...多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)及哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin,mTOR)作为细胞能量感受器是其中两个关键靶点。二者在PCOS各个发病部位包括下丘脑-垂体-卵巢轴、子宫内膜、脂肪与骨骼肌中发挥重要的调节作用,通过影响细胞自噬、氧化应激、炎症、线粒体功能、葡萄糖摄取等,促进卵泡的发育和成熟,改善胰岛素抵抗。近年来,中医药因其成分多样、靶点众多等优势广泛应用于临床,研究人员已对PCOS的发病以及中药治疗及改善PCOS的机制进行了大量研究,结果提示AMPK与mTOR相关通路在其中发挥关键作用。通过总结中药干预AMPK与mTOR及其相关通路治疗PCOS的研究结果,为临床治疗及基础研究提供参考。展开更多
Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuro...Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.展开更多
Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials i...Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2(HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR(PAM) pathway.展开更多
AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclospori...AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation(OLT), including all liver recipients with worsening renal function before conversion to mTORi(n = 55 patients) and recipients with normal renal function who converted to m TORi for other reasons(n = 31 patients). We identified patients with diabetes mellitus(n = 28), arterial hypertension(n = 27), proteinuria(n = 27) and all three factors(n = 8)(some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus(DM), hypertension(HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function(2.14 to 1.77 mg/dL)(P = 0.02). Patients with DM showed no improvement of serum creatinine levels(1.31 mg/dL to 1.37 mg/dL) compared with non DM patients(1.31 mg/dL to 1.15 mg/dL)(P = 0.01), HT patients(1.48 mg/dL to 1.5 mg/dL) with non HT patients(1.21mg/d L to 1.08 mg/dL) and patients with proteinuria(1.44 mg/dL to 1.41 mg/dL) and no proteinuria(1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to m TORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to m TORi; it also stabilizes renal function. Conversion to m TORi should only be avoided in patients with diabetes, hypertension and proteinuria.展开更多
目的:探讨肿瘤微环境中神经元对胶质瘤细胞迁移能力的影响。方法:分离培养胚胎18 d(E18)大鼠神经元,利用表达靶向神经连接蛋白3(NLGN3)分子shRNA的重组慢病毒(Lv-NLGN3-shRNA)感染神经元,real time RT-PCR和酶联免疫吸附试验(ELISA)检测...目的:探讨肿瘤微环境中神经元对胶质瘤细胞迁移能力的影响。方法:分离培养胚胎18 d(E18)大鼠神经元,利用表达靶向神经连接蛋白3(NLGN3)分子shRNA的重组慢病毒(Lv-NLGN3-shRNA)感染神经元,real time RT-PCR和酶联免疫吸附试验(ELISA)检测NLGN3的表达,收集神经元培养上清与胶质瘤细胞系U251细胞共培养,Transwell实验检测U251细胞迁移能力,Western Blot方法检测U251细胞中哺乳动物雷帕霉素靶蛋白(mTOR)和基质金属蛋白酶-9(MMP-9)的表达。结果:Lv-NLGN3-shRNA重组慢病毒感染能够降低大鼠原代神经元中NLGN3 mRNA和蛋白的的表达,神经元培养上清与U251细胞共培养可以增加后者的迁移能力并上调mTOR和MMP-9的表达。然而,NLGN3表达被Lv-NLGN3-shRNA抑制后,培养上清对U251细胞促迁移能力下降,同时mTOR和MMP-9表达降低。结论:大鼠原代神经元可以通过NLGN3/mTOR/MMP-9信号通路增强U251细胞的迁移能力,这一途径可能是胶质瘤细胞转移的机制之一。展开更多
文摘BACKGROUND Mammalian target of rapamycin(mTOR)inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma(HCC).However,their role in established post-transplant HCC recurrence is uncertain.AIM To investigate whether mTOR inhibitor offers a survival benefit in posttransplant HCC recurrence.METHODS A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed.They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression.The primary endpoint was post-recurrence survival.RESULTS Seventy-nine(55%)patients received an mTOR inhibitor-based immunosuppressive regime,while 64(45%)patients did not.The mTOR inhibitor group had a lower number of recurrent tumours(2 vs 5,P=0.02)and received more active treatments including radiotherapy(39 vs 22%,P=0.03)and targeted therapy(59 vs 23%,P<0.001).The median post-recurrence survival was 21.0±4.1 mo in the mTOR inhibitor group and 11.2±2.5 mo in the control group.Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival(P=0.04,OR=0.482,95%CI:0.241-0.966).The number of recurrent tumours and use of other treatment modalities did not affect survival.No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor.CONCLUSION mTOR inhibitors prolonged survival after post-transplant HCC recurrence.
文摘Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reported as altered in neuroendocrine tumors(NETs). m TOR inhibitors used in clinical practice are derived from rapamycin,an anti-cancer agent also used as an immunosuppressor after organ transplantation. Everolimus and temsirolimus are the two rapamycin-derived m TOR inhibitors used in NETs. Notably everolimus has been approved in advanced progressive well/moderatelydifferentiated pancreatic NETs(p NETs). It inhibits specifically the m TORC1 subunit of m TOR,not interacting with m TORC2. Although everolimus produced a significant prolongation of progression-free survival a number of patients with p NETs do not benefit from the drug due to early or late progression. Two supposed mechanisms of resistance to m TOR inhibitors are Akt and PI3 K activation,by means of m TORC2 and insulin growth factor(IGF)- IGF receptor signaling,respectively. BEZ235 is a multi-targeted inhibitor binding to PI3 K,m TORC1 and m TORC2,therefore potentially turning off all the supposed molecular targets of resistance to everolimus. The two clinical trials designed in p NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was also halted. Tolerability of this drug was challenging and conditioned the feasibility of therapy. The BEZ experience is an example of the huge difference between the preclinical and clinical setting and prompts us to pay more attention to the phase Ⅰ step of clinical development and the design of phase Ⅱ clinical trials.
文摘AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin(m TOR) inhibitors with or without calcineurin inhibitors(CNIs) in renal transplant recipients.METHODS We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, m TOR inhibitors as an alternative to CNI within six months of renal transplant by searching the Pub Med, EMBASE, Cochrane, Crossref, and Scopus using Me SH terms. RESULTS Six articles of early withdrawal of CNI and introduction of m TOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate(GFR) and serum creatinine were significantly better in m TOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in m TOR-inhibitor group. CONCLUSION The evidence reviewed in this meta-analysis suggests that early introduction m TOR-inhibitors substantial CNI minimization. The m TOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.
文摘Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Recognition of the molecular and cellular pathways that induce IBD is an emerging subject to develop targeted therapies.Mammalian target of rapamycin(mTOR)is one the most common receptors of many inflammatory pathways,including that of IBD.To this end,we intend to overview the mTOR inhibitors for their possible efficacy in present and future approaches to treatment of IBD.
文摘多囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一组生殖内分泌代谢紊乱的综合征,临床以稀发排卵、高雄激素体征、胰岛素抵抗为主要特征,其中育龄期发病率高,对女性生育力造成严重不良影响。PCOS的发生发展涉及多种信号通路,腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)及哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin,mTOR)作为细胞能量感受器是其中两个关键靶点。二者在PCOS各个发病部位包括下丘脑-垂体-卵巢轴、子宫内膜、脂肪与骨骼肌中发挥重要的调节作用,通过影响细胞自噬、氧化应激、炎症、线粒体功能、葡萄糖摄取等,促进卵泡的发育和成熟,改善胰岛素抵抗。近年来,中医药因其成分多样、靶点众多等优势广泛应用于临床,研究人员已对PCOS的发病以及中药治疗及改善PCOS的机制进行了大量研究,结果提示AMPK与mTOR相关通路在其中发挥关键作用。通过总结中药干预AMPK与mTOR及其相关通路治疗PCOS的研究结果,为临床治疗及基础研究提供参考。
基金supported by the National Natural Science Foundation of China,No.81401004(to XGL)Medical and Health Technology Development Program of Zhejiang Province of China,No.2015-KY1001-036(to XGL)
文摘Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.
文摘Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2(HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR(PAM) pathway.
文摘AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation(OLT), including all liver recipients with worsening renal function before conversion to mTORi(n = 55 patients) and recipients with normal renal function who converted to m TORi for other reasons(n = 31 patients). We identified patients with diabetes mellitus(n = 28), arterial hypertension(n = 27), proteinuria(n = 27) and all three factors(n = 8)(some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus(DM), hypertension(HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function(2.14 to 1.77 mg/dL)(P = 0.02). Patients with DM showed no improvement of serum creatinine levels(1.31 mg/dL to 1.37 mg/dL) compared with non DM patients(1.31 mg/dL to 1.15 mg/dL)(P = 0.01), HT patients(1.48 mg/dL to 1.5 mg/dL) with non HT patients(1.21mg/d L to 1.08 mg/dL) and patients with proteinuria(1.44 mg/dL to 1.41 mg/dL) and no proteinuria(1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to m TORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to m TORi; it also stabilizes renal function. Conversion to m TORi should only be avoided in patients with diabetes, hypertension and proteinuria.
