BACKGROUND: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients an...BACKGROUND: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups. DATA SOURCES: A computer-based systematic search from January 2005 to June 2011 with 'sorafenib' and 'advanced hepatocellular carcinoma' as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0). RESULTS: Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/ placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation.CONCLUSIONS: Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.展开更多
Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ...Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).展开更多
Magnesium has been suggested as a revolutionary biodegradable metal for biomedical applications. The corrosion of magnesium, however, is too rapid to match the rates of tissue healing and, additionally, exhibits the l...Magnesium has been suggested as a revolutionary biodegradable metal for biomedical applications. The corrosion of magnesium, however, is too rapid to match the rates of tissue healing and, additionally, exhibits the localized corrosion mechanism. Thus it is necessary to control the corrosion behaviors of magnesium for their practical use. This paper comprehensively reviews the research progress on the development of representative magnesium based alloys, including Mg-Ca, Mg-Sr, Mg-Zn and Mg-REE alloy systems as well as the bulk metallic glass. The influence of alloying element on their microstructures, mechanical properties and corrosion behaviors is summarized. The mechanical and corrosion properties of wrought magnesium alloys are also discussed in comparison with those of cast alloys. Furthermore, this review also covers research carried out in the field of the degradable coatings on magnesium alloys for biomedical applications. Calcium phosphate and biodegradable polymer coatings are discussed based on different preparation techniques used. We also compare the effect of different coatings on the corrosion behaviors of magnesium alloys substrate.展开更多
As China’s first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band(1-250 ke V) slat-collimator-based X-ray as...As China’s first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band(1-250 ke V) slat-collimator-based X-ray astronomy satellite with the capability of all-sky monitoring in 0.2-3 Me V. It was designed to perform pointing, scanning and gamma-ray burst(GRB)observations and, based on the Direct Demodulation Method (DDM), the image of the scanned sky region can be reconstructed.Here we give an overview of the mission and its progresses, including payload, core sciences, ground calibration/facility, ground segment, data archive, software, in-orbit performance, calibration, background model, observations and some preliminary results.展开更多
The membrane-associated transcription factor, bZlP28, is relocated from the endoplasmic reticulum （ER） to the Golgi and proteolytically released from the membrane mediated by two proteases, SlP and S2P, in response ...The membrane-associated transcription factor, bZlP28, is relocated from the endoplasmic reticulum （ER） to the Golgi and proteolytically released from the membrane mediated by two proteases, SlP and S2P, in response to ER stress in Arabidopsis. The activated N-terminal domain recruits nuclear factor Y （NF-Y） subunits in the nucleus to regulate ER stress downstream genes. Little is known about the functions of the bZIP28 C-terminal lumen-facing domain. Here, we provide novel insights into how the ER lumen-facing domain affects the biological function and organelle-to-organelle movement of bZIP28 in the ER stress response. First, we demonstrated the functional redundancy of bZlP28 and bZIP60 by generation and analysis of the bZIP28 and bZIP60 double mutant zip28zip60. Subsequent genetic complementation experiments in zip28zip60 background with deletions on bZlP28 lumen-facing domain highlighted the importance of lumen-facing domain for its in vivo function of bZIP28 in the ER stress response. The protein subcellular localization and Western blotting results further revealed that the bZIP28 lumen-facing domain contains ER retention signal which is important for the proteolytic activation of bZIP28. Thus, the bZIP28 lumen-facing C-terminus plays important roles in the ER-to-Golgi movement of bZlP28, which may contribute to the sensing of the ER stress.展开更多
Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis a...Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system （Shanghai Score） for individualized prognosis estimation and adjuvant treatment evaluation. Methods： A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, y-glutamyltransferase, a-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell＇s concordance index （C-index） was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable＇s corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis.Results： Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index （confidence interval [CI]） was 0.74 for overall survival （OS） and 0.68 for recurrence-free survival （RFS） in derivation cohort （4166 patients）, and in the three independent validation cohorts, the CIs for OS ranged 0.70 0.72 and that for RFS ranged 0.63 0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices （transcatheter arterial chemo展开更多
Background Baicalin has a significant anti-inflammation effect and is widely used in the clinical treatment of stroke. Most of the studies of Toll-like receptor 2/4 （TLR2/4） during cerebral ischemia had defined the...Background Baicalin has a significant anti-inflammation effect and is widely used in the clinical treatment of stroke. Most of the studies of Toll-like receptor 2/4 （TLR2/4） during cerebral ischemia had defined their specific expressions in microglia in hippocampus tissue. To explore the targets of baicalin in stroke, we detected the expressions of TLR2/4 in vitro/vivo.Methods By constructing a cerebral ischemia-reperfusion model in vivo and glucose oxygen deprivation model, we successfully induced neuron damage, then added baicalin and detected expressions of TLR2/4, nuclear factor-kB （NF-kB）, tumor necrosis factor-alpha （TNFα）, and interleukin-1β （IL-1β） in mRNA level and protein level.Results We found distinct upregulations of TLR2/4 and TNFα in both mRNA level and protein level in PC12 cells and primary neurons. Moreover, TLR2/4 and TNFα expressions were significantly higher in mice hippocampus treated with cerebral ischemia-reperfusion. Baicalin could downregulate the expressions of TLR2/4 and TNFα in the damaged cells and mice hippocampus effectively.Conclusions Neurons could respond to the damage and activate the related signal pathway directly. TLR2/4 responsed to the damage and sent the signal to downstream factor TNFα through activating NF-kB. Baicalin could inhibit the inflammatory reaction in neuron damage and TLR might be its targets, which explained why baicalin could widely be used in the clinical treatment of stroke.展开更多
基金supported by grants from the National Natural Science Foundation of China(30700815,30972949 and 81000927)Shanghai Key-Tech Research&Development Program(09411951700)+1 种基金Program for Shanghai Excellent Subject Leaders(10XD1401200)the Research Fund for the Doctoral Program of Higher Education of China(20100071120064)
文摘BACKGROUND: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups. DATA SOURCES: A computer-based systematic search from January 2005 to June 2011 with 'sorafenib' and 'advanced hepatocellular carcinoma' as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0). RESULTS: Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/ placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation.CONCLUSIONS: Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.
基金National Natural Science Foundation of China(81972232,81830102,82150004)Clinical Research Plan of SHDC(SHDC‑2020CR1003A,SHDC-2020CR1022B)+3 种基金National Key Research and Development Program of China(2019YFC1316000,2019YFC1315800,and 2019YFC1315802)the Key Disease Joint Research Program of Xuhui District(XHLHGG202103),the Clinical Medicine Research Pilot Project of Shanghai Medical School of Fudan University(2020,21DGF501035/00)the Shanghai Municipal Natural Science Foundation(20JC1419103,21ZR1412200)Beijing Mutual Care Public Welfare Foundation(GDXZ-08-05)Sanming Project of Medicine in Shenzhen(SZSM202003009),and Shanghai Municipal Key Clinical Specialty Construction Project(shslczdzk02401).
文摘Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).
基金Acknowledgements This work was supported by the National Basic Research Program of China （973 Program） （Grant Nos. 2012CB619102 and 2012CB619100）, Specialized Research Fund for the Doctoral Program of Higher Education under Grant No. 20121102120037, the National Natural Science Foundation of China （Grant No. 31370959）, Fok Ying Tong Education Foundation （Grant No. 141039）, and Beijing Natural Science Foundation （Grant No. 7142094）. Xuenan would like to thank Dr. Fuzhai Cui at Tsinghua University for the kindly invitation of this review.
文摘Magnesium has been suggested as a revolutionary biodegradable metal for biomedical applications. The corrosion of magnesium, however, is too rapid to match the rates of tissue healing and, additionally, exhibits the localized corrosion mechanism. Thus it is necessary to control the corrosion behaviors of magnesium for their practical use. This paper comprehensively reviews the research progress on the development of representative magnesium based alloys, including Mg-Ca, Mg-Sr, Mg-Zn and Mg-REE alloy systems as well as the bulk metallic glass. The influence of alloying element on their microstructures, mechanical properties and corrosion behaviors is summarized. The mechanical and corrosion properties of wrought magnesium alloys are also discussed in comparison with those of cast alloys. Furthermore, this review also covers research carried out in the field of the degradable coatings on magnesium alloys for biomedical applications. Calcium phosphate and biodegradable polymer coatings are discussed based on different preparation techniques used. We also compare the effect of different coatings on the corrosion behaviors of magnesium alloys substrate.
基金project funded by China National Space Administration(CNSA)and the Chinese Academy of Sciences(CAS)support from the National Key Research and Development Program of China(Grant No.2016YFA0400800)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant Nos.XDA04010202,XDA04010300,and XDB23040400)the National Natural Science Foundation of China(Grant Nos.U1838201,and U1838102).
文摘As China’s first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band(1-250 ke V) slat-collimator-based X-ray astronomy satellite with the capability of all-sky monitoring in 0.2-3 Me V. It was designed to perform pointing, scanning and gamma-ray burst(GRB)observations and, based on the Direct Demodulation Method (DDM), the image of the scanned sky region can be reconstructed.Here we give an overview of the mission and its progresses, including payload, core sciences, ground calibration/facility, ground segment, data archive, software, in-orbit performance, calibration, background model, observations and some preliminary results.
基金This study was financially supported by grants from the National Basic Research Program of China （973 Program, 2012CB910500）, the National Natural Science Foundation of China （#31171157 #31070233 #31222008）, and the Shanghai Pujiang Talent Program （11PJ1400700）. No conflict of interest declared.
文摘The membrane-associated transcription factor, bZlP28, is relocated from the endoplasmic reticulum （ER） to the Golgi and proteolytically released from the membrane mediated by two proteases, SlP and S2P, in response to ER stress in Arabidopsis. The activated N-terminal domain recruits nuclear factor Y （NF-Y） subunits in the nucleus to regulate ER stress downstream genes. Little is known about the functions of the bZIP28 C-terminal lumen-facing domain. Here, we provide novel insights into how the ER lumen-facing domain affects the biological function and organelle-to-organelle movement of bZIP28 in the ER stress response. First, we demonstrated the functional redundancy of bZlP28 and bZIP60 by generation and analysis of the bZIP28 and bZIP60 double mutant zip28zip60. Subsequent genetic complementation experiments in zip28zip60 background with deletions on bZlP28 lumen-facing domain highlighted the importance of lumen-facing domain for its in vivo function of bZIP28 in the ER stress response. The protein subcellular localization and Western blotting results further revealed that the bZIP28 lumen-facing domain contains ER retention signal which is important for the proteolytic activation of bZIP28. Thus, the bZIP28 lumen-facing C-terminus plays important roles in the ER-to-Golgi movement of bZlP28, which may contribute to the sensing of the ER stress.
基金This study was supported by grants from the National High Technology Research and Development Program （863 Program） of China （No. 2015AA020401）, National Key Research and Development Program of China （No. 2016YFC0904101）, State Key Program of National Natural Science Foundation of China （No. 81530077）, National Natural Science Foundation of China （No. 81372317, 81472676, and 81572823）, Projects from the Shanghai Science and Technology Commission （No. 14DZ1940300, 14411970200, 134119a1201, and 14140902301）, and Specialized Research Fund for the Doctoral Program of Higher Education and Research Grants Council Earmarked Research Grants Joint Research Scheme （No. 20130071140008）.
文摘Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system （Shanghai Score） for individualized prognosis estimation and adjuvant treatment evaluation. Methods： A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, y-glutamyltransferase, a-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell＇s concordance index （C-index） was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable＇s corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis.Results： Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index （confidence interval [CI]） was 0.74 for overall survival （OS） and 0.68 for recurrence-free survival （RFS） in derivation cohort （4166 patients）, and in the three independent validation cohorts, the CIs for OS ranged 0.70 0.72 and that for RFS ranged 0.63 0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices （transcatheter arterial chemo
基金This work was supported by grants from the National Natural Science Foundation of China （No. 30973896, No. 30801523, and No. 81073092） and the National S＆T Major Special Project for New Drug R＆D Program of China （No. 2009ZX09103-301, No. 2009ZX09502, No. 2009ZX09308-003, and No. 2011ZX09101- 002-11）.Acknowledgments： We thank specially all our colleagues in our laboratory.
文摘Background Baicalin has a significant anti-inflammation effect and is widely used in the clinical treatment of stroke. Most of the studies of Toll-like receptor 2/4 （TLR2/4） during cerebral ischemia had defined their specific expressions in microglia in hippocampus tissue. To explore the targets of baicalin in stroke, we detected the expressions of TLR2/4 in vitro/vivo.Methods By constructing a cerebral ischemia-reperfusion model in vivo and glucose oxygen deprivation model, we successfully induced neuron damage, then added baicalin and detected expressions of TLR2/4, nuclear factor-kB （NF-kB）, tumor necrosis factor-alpha （TNFα）, and interleukin-1β （IL-1β） in mRNA level and protein level.Results We found distinct upregulations of TLR2/4 and TNFα in both mRNA level and protein level in PC12 cells and primary neurons. Moreover, TLR2/4 and TNFα expressions were significantly higher in mice hippocampus treated with cerebral ischemia-reperfusion. Baicalin could downregulate the expressions of TLR2/4 and TNFα in the damaged cells and mice hippocampus effectively.Conclusions Neurons could respond to the damage and activate the related signal pathway directly. TLR2/4 responsed to the damage and sent the signal to downstream factor TNFα through activating NF-kB. Baicalin could inhibit the inflammatory reaction in neuron damage and TLR might be its targets, which explained why baicalin could widely be used in the clinical treatment of stroke.
