While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered selfrepairingautophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hy...While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered selfrepairingautophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel(NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundantNO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles(MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtainMNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability toperform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distributionand strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and thisprocess is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over onemonth and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel atthe tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NOeffectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronouslydestroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26colon tumors are completely eliminated without causing severe side-effects.展开更多
Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neur...Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia（33°C） was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling（TUNEL） staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the m RNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.展开更多
目的研究连续性神经元特异性烯醇化酶(NSE)监测是否可预测心脏骤停(CA)后亚低温治疗(MHT)患者短期及远期神经功能预后。方法前瞻性收集2013年6月至2017年11月江苏大学附属医院ICU收治的CA后恢复自主循环并且MHT的患者共计130例,收集患...目的研究连续性神经元特异性烯醇化酶(NSE)监测是否可预测心脏骤停(CA)后亚低温治疗(MHT)患者短期及远期神经功能预后。方法前瞻性收集2013年6月至2017年11月江苏大学附属医院ICU收治的CA后恢复自主循环并且MHT的患者共计130例,收集患者的一般临床资料,监测入科第1、2、3、4天NSE值,观察30d神经功能预后及6个月神经功能预后,根据脑功能分级(CPC)将30 d CPC1~2级者定为A组,30 d CPC3~5级定为B组,6个月CPC1~2级定为C组,6个月CPC3~5级定为D组,分别比较各时间点A、B两组及C、D两组NSE值,同时采用ROC曲线分析每天NSE值是否与短期及长期预后存在相关性。结果①A、B两组及C、D两组分别进行组间比较,一般临床资料如性别、年龄、CA原因、CA前心律、APACHEⅡ评分、初始乳酸水平比较差异无统计学意义(P>0.05);②A、B两组比较,第1天A组NSE值为(60.32±14.00)ng/mL,B组NSE值为(69.04±20.91)ng/mL;第2天A组NSE值为(84.63±9.01)ng/mL,B组NSE值为(101.65±15.07)ng/mL;第3天A组NSE值为(57.35±13.03)ng/mL,B组NSE值为(72.51±6.85)ng/mL;第4天A组NSE值为(48.84±12.34)ng/mL,B组NSE值为(62.73±12.03)ng/mL;各时间点A组NSE明显低于B组(P<0.05);C、D两组比较,第1天C组NSE值为(57.66±10.13)ng/mL,D组NSE值为(68.51±20.66)ng/mL,第2天C组NSE值为(85.41±9.08)ng/mL,D组NSE值为(97.30±15.98)ng/mL,第3天C组NSE值为(56.26±11.81)ng/mL,D组NSE值为(66./9±14.17)ng/mL,第4天C组NSE值为(48.81±10.92)ng/mL,D组NSE值为(57.43±12.60)ng/mL,各时间点C组NSE明显低于D组(P<0.05)。③通过ROC曲线分析,预测30dCPC值,第1天的ROC曲线下面积(AUC)0.624(P<0.05),第2天AUC0.903(P<0.001),第3天AUC0.920(P<0.001),第4天AUC0.905(P<0.001),均对预后有预测意义。④通过ROC曲线分析,预测6个月CPC值,第1天AUC 0.651(P<0.05),第2天AUC0.773(P<0.001),第3天AUC0.798(P<0.001),第4天AUC0.788(P<0.001),均对预后有预测意义。结论对于CA后MHT患者,动态监测NSE值可预测短期及长期神经功能预后。展开更多
基金supported by the National Natural Science Foundation of China(grant no.21975045)Natural Science Foundation of Shanghai(grant no.23ZR1406800).
文摘While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered selfrepairingautophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel(NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundantNO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles(MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtainMNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability toperform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distributionand strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and thisprocess is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over onemonth and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel atthe tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NOeffectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronouslydestroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26colon tumors are completely eliminated without causing severe side-effects.
基金supported by the National Natural Science Foundation of China,No.81371301
文摘Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia（33°C） was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling（TUNEL） staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the m RNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.
文摘目的研究连续性神经元特异性烯醇化酶(NSE)监测是否可预测心脏骤停(CA)后亚低温治疗(MHT)患者短期及远期神经功能预后。方法前瞻性收集2013年6月至2017年11月江苏大学附属医院ICU收治的CA后恢复自主循环并且MHT的患者共计130例,收集患者的一般临床资料,监测入科第1、2、3、4天NSE值,观察30d神经功能预后及6个月神经功能预后,根据脑功能分级(CPC)将30 d CPC1~2级者定为A组,30 d CPC3~5级定为B组,6个月CPC1~2级定为C组,6个月CPC3~5级定为D组,分别比较各时间点A、B两组及C、D两组NSE值,同时采用ROC曲线分析每天NSE值是否与短期及长期预后存在相关性。结果①A、B两组及C、D两组分别进行组间比较,一般临床资料如性别、年龄、CA原因、CA前心律、APACHEⅡ评分、初始乳酸水平比较差异无统计学意义(P>0.05);②A、B两组比较,第1天A组NSE值为(60.32±14.00)ng/mL,B组NSE值为(69.04±20.91)ng/mL;第2天A组NSE值为(84.63±9.01)ng/mL,B组NSE值为(101.65±15.07)ng/mL;第3天A组NSE值为(57.35±13.03)ng/mL,B组NSE值为(72.51±6.85)ng/mL;第4天A组NSE值为(48.84±12.34)ng/mL,B组NSE值为(62.73±12.03)ng/mL;各时间点A组NSE明显低于B组(P<0.05);C、D两组比较,第1天C组NSE值为(57.66±10.13)ng/mL,D组NSE值为(68.51±20.66)ng/mL,第2天C组NSE值为(85.41±9.08)ng/mL,D组NSE值为(97.30±15.98)ng/mL,第3天C组NSE值为(56.26±11.81)ng/mL,D组NSE值为(66./9±14.17)ng/mL,第4天C组NSE值为(48.81±10.92)ng/mL,D组NSE值为(57.43±12.60)ng/mL,各时间点C组NSE明显低于D组(P<0.05)。③通过ROC曲线分析,预测30dCPC值,第1天的ROC曲线下面积(AUC)0.624(P<0.05),第2天AUC0.903(P<0.001),第3天AUC0.920(P<0.001),第4天AUC0.905(P<0.001),均对预后有预测意义。④通过ROC曲线分析,预测6个月CPC值,第1天AUC 0.651(P<0.05),第2天AUC0.773(P<0.001),第3天AUC0.798(P<0.001),第4天AUC0.788(P<0.001),均对预后有预测意义。结论对于CA后MHT患者,动态监测NSE值可预测短期及长期神经功能预后。
