Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected pa...Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.展开更多
目的观察白虎加人参汤对2型糖尿病(type 2 diabetes mellitus,T2DM)MKR小鼠肠道解偶联蛋白2(uncoupling protein 2,UCP2)、AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)表达及胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)...目的观察白虎加人参汤对2型糖尿病(type 2 diabetes mellitus,T2DM)MKR小鼠肠道解偶联蛋白2(uncoupling protein 2,UCP2)、AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)表达及胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)分泌的影响,探讨其降糖机制。方法将MKR小鼠随机分为模型组和白虎加人参汤低、高剂量组,以FVB小鼠为空白组,中药干预4周后,观察小鼠糖代谢变化;ELISA法检测小鼠血清中胰岛素(insulin,INS)、GLP-1水平;RT-qPCR检测小鼠结肠AMPK、UCP2 mRNA水平;Western blot法检测小鼠结肠P-AMPKα、UCP2蛋白表达水平;组织形态学观察小鼠结肠组织病理形态及黏液量的变化。结果白虎加人参汤低、高剂量组与模型组比较,均能显著降低MKR小鼠的空腹血糖和INS水平(P<0.01);并能提高血清GLP-1浓度(P<0.01,P<0.05);上调小鼠结肠AMPK mRNA和P-AMPKα水平(P<0.01),下调UCP2 mRNA和蛋白水平(P<0.01)。白虎加人参汤低、高剂量组均能明显改善MKR小鼠结肠组织病理形态。结论白虎加人参汤可能通过抑制UCP2表达、激活AMPK的表达,促进肠道GLP-1的分泌,发挥治疗T2DM的作用。展开更多
The Paleoproterozoic Liiliang Metamorphic Complex （PLMC） is situated in the middle segment of the western margin of the Trans-North China Orogen （TNCO）, North China Craton （NCC）. As the most important lithologic...The Paleoproterozoic Liiliang Metamorphic Complex （PLMC） is situated in the middle segment of the western margin of the Trans-North China Orogen （TNCO）, North China Craton （NCC）. As the most important lithological assemblages in the southern part of the PLMC, Guandishan granitoids consist of early gneissic tonalities, granodiorites and gneissic monzogranites, and younger gneissic to massive monzogranites. Petrochemical features reveal that the early gneissic tonalities and granodiorites belong to the medium-K calc-alkaline series; the early gneissic monzogranites are transitional from high-K calc-alkaline to the shoshonite series; the younger gneissic to massive monzogranites belong to the high-k calc-alkaline series, and all rocks are characterized by right- declined REE patterns and negative Nb, Ta, Sr, P, and Ti anomalies in the primitive mantle normalized spidergrams. SHRIMP zircon U-Pb isotopic dating reveals that the early gneissic tonalities and granodiorites formed at -2.17 Ga, the early gneissic monzogranites at -2.06 Ga, and the younger gneissic to massive monzogranites at -1.84 Ga. Sm-Nd isotopic data show that the early gneissic tonalities and granodiorites have eNd（t） values of ＋0.48 to -3.19 with Nd-depleted mantle model ages （TDM） of 2.76--2.47 Ga, and early gneissic monzogranites have eNd（t） values of -0.53 to -2.51 with TDM of 2.61--2.43 Ga, and the younger gneissic monzogranites have eNd（t） values of -6.41 to -2.78 with a TDM of 2.69--2.52 Ga.These geochemical and isotopic data indicate that the early gneissic tonalities, granodiorites, and monzogranites were derived from the partial melting of metamorphosed basaltic and pelitic rocks, respectively, in a continental arc setting. The younger gneissic to massive monzogranites were derived by partial melting of metamorphosed greywackes within the continental crust. Combined with previously regional data, we suggest that the Paleoproterozoic granitoid magmatism in the Guandishan granitoids of the PLMC may provide the be展开更多
A new method for estimating significant wave height（SWH） from advanced synthetic aperture radar（ASAR） wave mode data based on a support vector machine（SVM） regression model is presented. The model is established...A new method for estimating significant wave height（SWH） from advanced synthetic aperture radar（ASAR） wave mode data based on a support vector machine（SVM） regression model is presented. The model is established based on a nonlinear relationship between σ0, the variance of the normalized SAR image, SAR image spectrum spectral decomposition parameters and ocean wave SWH. The feature parameters of the SAR images are the input parameters of the SVM regression model, and the SWH provided by the European Centre for Medium-range Weather Forecasts（ECMWF） is the output parameter. On the basis of ASAR matching data set, a particle swarm optimization（PSO） algorithm is used to optimize the input kernel parameters of the SVM regression model and to establish the SVM model. The SWH estimation results yielded by this model are compared with the ECMWF reanalysis data and the buoy data. The RMSE values of the SWH are 0.34 and 0.48 m, and the correlation coefficient is 0.94 and 0.81, respectively. The results show that the SVM regression model is an effective method for estimating the SWH from the SAR data. The advantage of this model is that SAR data may serve as an independent data source for retrieving the SWH, which can avoid the complicated solution process associated with wave spectra.展开更多
Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.H...Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.展开更多
Early insulin therapy is capable to achieve glycemic control and restoreβ-cell function in newly diagnosed type 2 diabetes(T2D),but its effect on cardiovascular outcomes in these patients remains unclear.In this nati...Early insulin therapy is capable to achieve glycemic control and restoreβ-cell function in newly diagnosed type 2 diabetes(T2D),but its effect on cardiovascular outcomes in these patients remains unclear.In this nationwide real-world study,we analyzed electronic health record data from 19 medical centers across China between 1 January 2000,and 26 May 2022.We included 5424 eligible patients(mean age 56 years,2176 women/3248 men)who were diagnosed T2D within six months and did not have prior cardiovascular disease.Multivariable Cox regression models were used to estimate the associations of early insulin therapy(defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients)with the incidence of major cardiovascular events including coronary heart disease(CHD),stroke,and hospitalization for heart failure(HF).During 17,158 persons years of observation,we documented 834 incident CHD cases,719 stroke cases,and 230 hospitalized cases for HF.Newly diagnosed T2D patients who received early insulin therapy,compared with those who did not receive such treatment,had 31%lower risk of incident stroke,and 28%lower risk of hospitalization for HF.No significant difference in the risk of CHD was observed.We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models.These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.展开更多
We demonstrate a novel flat-field,dual-optic imaging EUV—soft X-ray spectrometer and monochromator that attains an unprecedented throughput efficiency exceeding 60%by design,along with a superb spectral resolution of...We demonstrate a novel flat-field,dual-optic imaging EUV—soft X-ray spectrometer and monochromator that attains an unprecedented throughput efficiency exceeding 60%by design,along with a superb spectral resolution ofλ/Δλ>200 accomplished without employing variable line spacing gratings.Exploiting the benefits of the conical diffraction geometry,the optical system is globally optimized in multidimensional parameter space to guarantee optimal imaging performance over a broad spectral range while maintaining circular and elliptical polarization states at the first,second,and third diffraction orders.Moreover,our analysis indicates minimal temporal dispersion,with pulse broadening confined within 80 fs tail-to-tail and an FWHM value of 29 fs,which enables ultrafast spectroscopic and pump-probe studies with femtosecond accuracy.Furthermore,the spectrometer can be effortlessly transformed into a monochromator spanning the EUV—soft X-ray spectral region using a single grating with an aberration-free spatial profile.Such capability allows coherent diffractive imaging applications to be conducted with highly monochromatic light in a broad spectral range and extended to the soft X-ray region with minimal photon loss,thus facilitating state-of-the-art imaging of intricate nano-and bio-systems,with a significantly enhanced spatiotemporal resolution,down to the nanometer–femtosecond level.展开更多
文摘Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.
文摘目的观察白虎加人参汤对2型糖尿病(type 2 diabetes mellitus,T2DM)MKR小鼠肠道解偶联蛋白2(uncoupling protein 2,UCP2)、AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)表达及胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)分泌的影响,探讨其降糖机制。方法将MKR小鼠随机分为模型组和白虎加人参汤低、高剂量组,以FVB小鼠为空白组,中药干预4周后,观察小鼠糖代谢变化;ELISA法检测小鼠血清中胰岛素(insulin,INS)、GLP-1水平;RT-qPCR检测小鼠结肠AMPK、UCP2 mRNA水平;Western blot法检测小鼠结肠P-AMPKα、UCP2蛋白表达水平;组织形态学观察小鼠结肠组织病理形态及黏液量的变化。结果白虎加人参汤低、高剂量组与模型组比较,均能显著降低MKR小鼠的空腹血糖和INS水平(P<0.01);并能提高血清GLP-1浓度(P<0.01,P<0.05);上调小鼠结肠AMPK mRNA和P-AMPKα水平(P<0.01),下调UCP2 mRNA和蛋白水平(P<0.01)。白虎加人参汤低、高剂量组均能明显改善MKR小鼠结肠组织病理形态。结论白虎加人参汤可能通过抑制UCP2表达、激活AMPK的表达,促进肠道GLP-1的分泌,发挥治疗T2DM的作用。
基金support forthis study was provided by the National Natural ScienceFoundation of China(No.:40821002,40872120,40420120135,40472096,and 40472118)
文摘The Paleoproterozoic Liiliang Metamorphic Complex （PLMC） is situated in the middle segment of the western margin of the Trans-North China Orogen （TNCO）, North China Craton （NCC）. As the most important lithological assemblages in the southern part of the PLMC, Guandishan granitoids consist of early gneissic tonalities, granodiorites and gneissic monzogranites, and younger gneissic to massive monzogranites. Petrochemical features reveal that the early gneissic tonalities and granodiorites belong to the medium-K calc-alkaline series; the early gneissic monzogranites are transitional from high-K calc-alkaline to the shoshonite series; the younger gneissic to massive monzogranites belong to the high-k calc-alkaline series, and all rocks are characterized by right- declined REE patterns and negative Nb, Ta, Sr, P, and Ti anomalies in the primitive mantle normalized spidergrams. SHRIMP zircon U-Pb isotopic dating reveals that the early gneissic tonalities and granodiorites formed at -2.17 Ga, the early gneissic monzogranites at -2.06 Ga, and the younger gneissic to massive monzogranites at -1.84 Ga. Sm-Nd isotopic data show that the early gneissic tonalities and granodiorites have eNd（t） values of ＋0.48 to -3.19 with Nd-depleted mantle model ages （TDM） of 2.76--2.47 Ga, and early gneissic monzogranites have eNd（t） values of -0.53 to -2.51 with TDM of 2.61--2.43 Ga, and the younger gneissic monzogranites have eNd（t） values of -6.41 to -2.78 with a TDM of 2.69--2.52 Ga.These geochemical and isotopic data indicate that the early gneissic tonalities, granodiorites, and monzogranites were derived from the partial melting of metamorphosed basaltic and pelitic rocks, respectively, in a continental arc setting. The younger gneissic to massive monzogranites were derived by partial melting of metamorphosed greywackes within the continental crust. Combined with previously regional data, we suggest that the Paleoproterozoic granitoid magmatism in the Guandishan granitoids of the PLMC may provide the be
基金The National Key Research and Development Program of China under contract Nos 2016YFA0600102 and2016YFC1401007the National Natural Science Youth Foundation of China under contract No.61501130the Natural Science Foundation of China under contract No.41406207
文摘A new method for estimating significant wave height（SWH） from advanced synthetic aperture radar（ASAR） wave mode data based on a support vector machine（SVM） regression model is presented. The model is established based on a nonlinear relationship between σ0, the variance of the normalized SAR image, SAR image spectrum spectral decomposition parameters and ocean wave SWH. The feature parameters of the SAR images are the input parameters of the SVM regression model, and the SWH provided by the European Centre for Medium-range Weather Forecasts（ECMWF） is the output parameter. On the basis of ASAR matching data set, a particle swarm optimization（PSO） algorithm is used to optimize the input kernel parameters of the SVM regression model and to establish the SVM model. The SWH estimation results yielded by this model are compared with the ECMWF reanalysis data and the buoy data. The RMSE values of the SWH are 0.34 and 0.48 m, and the correlation coefficient is 0.94 and 0.81, respectively. The results show that the SVM regression model is an effective method for estimating the SWH from the SAR data. The advantage of this model is that SAR data may serve as an independent data source for retrieving the SWH, which can avoid the complicated solution process associated with wave spectra.
基金This study was financially supported by the National Key Research and Development Program of China(2022YFC2804100,2021YFF0502400,2022YFC2804300)National Natural Science Foundation of China(82073713,22137006,82104033,82173730,81903499,32070070,82160669)Innovative research team of highlevel local universities in Shanghai(SHSMU-ZDCX20212702,China).We thank Dr.Juncheng Su from Shanghai Jiao-Tong University School of Medicine(Shanghai,China)for providing the LoVo and COLO 320DM cell lines.
文摘Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
基金the National Key R&D Program of China(grant No.2021YFC2500501)the Strategic Priority Research Program of Chinese Academy of Sciences(grant no.XDB38010100)+4 种基金the National Natural Science Foundation of China(grant no.82030022 and 82330020)Program for Innovative Research Team of The First Affiliated Hospital of USTC(grant no.CXGG02)the Program of Introducing Talents of Discipline to Universities,111 Plan(grant no.D18005)Guangdong Provincial Clinical Research Center for Kidney Disease(2020B1111170013)Key Technologies R&D Program of Guangdong Province(grant no.2023B1111030004).
文摘Early insulin therapy is capable to achieve glycemic control and restoreβ-cell function in newly diagnosed type 2 diabetes(T2D),but its effect on cardiovascular outcomes in these patients remains unclear.In this nationwide real-world study,we analyzed electronic health record data from 19 medical centers across China between 1 January 2000,and 26 May 2022.We included 5424 eligible patients(mean age 56 years,2176 women/3248 men)who were diagnosed T2D within six months and did not have prior cardiovascular disease.Multivariable Cox regression models were used to estimate the associations of early insulin therapy(defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients)with the incidence of major cardiovascular events including coronary heart disease(CHD),stroke,and hospitalization for heart failure(HF).During 17,158 persons years of observation,we documented 834 incident CHD cases,719 stroke cases,and 230 hospitalized cases for HF.Newly diagnosed T2D patients who received early insulin therapy,compared with those who did not receive such treatment,had 31%lower risk of incident stroke,and 28%lower risk of hospitalization for HF.No significant difference in the risk of CHD was observed.We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models.These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.
基金funding from the National Key Research and Development Program of China(2021YFB3602600)the Chinese Academy of Sciences(CAS)(GJJSTD20200009)(2018-131-S)+3 种基金the National Natural Science Foundation of China(NSFC)(62121003)(10010108B1339-2451)the Beijing Municipal Science&Technology Commission(Z221100006722008)T.P.gratefully acknowledges funding from the European Research Council(ERC)(grant agreement XSTREAM-716950)the Alfred P.Sloan Foundation(FG-2018-10892)。
文摘We demonstrate a novel flat-field,dual-optic imaging EUV—soft X-ray spectrometer and monochromator that attains an unprecedented throughput efficiency exceeding 60%by design,along with a superb spectral resolution ofλ/Δλ>200 accomplished without employing variable line spacing gratings.Exploiting the benefits of the conical diffraction geometry,the optical system is globally optimized in multidimensional parameter space to guarantee optimal imaging performance over a broad spectral range while maintaining circular and elliptical polarization states at the first,second,and third diffraction orders.Moreover,our analysis indicates minimal temporal dispersion,with pulse broadening confined within 80 fs tail-to-tail and an FWHM value of 29 fs,which enables ultrafast spectroscopic and pump-probe studies with femtosecond accuracy.Furthermore,the spectrometer can be effortlessly transformed into a monochromator spanning the EUV—soft X-ray spectral region using a single grating with an aberration-free spatial profile.Such capability allows coherent diffractive imaging applications to be conducted with highly monochromatic light in a broad spectral range and extended to the soft X-ray region with minimal photon loss,thus facilitating state-of-the-art imaging of intricate nano-and bio-systems,with a significantly enhanced spatiotemporal resolution,down to the nanometer–femtosecond level.
