Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of lim...Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.展开更多
AIM: To investigate the effect of integrin-linked kinase (ILK) on proliferation, metastasis, and invasion of the colorectal cancer cell line SW480.METHODS: In this study, the colorectal cancer cell line SW480 was stab...AIM: To investigate the effect of integrin-linked kinase (ILK) on proliferation, metastasis, and invasion of the colorectal cancer cell line SW480.METHODS: In this study, the colorectal cancer cell line SW480 was stably transfected with ILK plasmids, and small interfering RNA (siRNA) was used to knockdown expression of nuclear factor (NF)-κB/p65. Methylthiazole tetrazolium (MTT) assay was performed to measure proliferation, and the wound healing migration assay and matrigel invasion assay were used to test the metastasis and invasion ability of SW480 cells. To explore the epithelial-mesenchymal transition (EMT) process, embryonic development, and the invasion and metastasis of tumors, the protein level of E-cadherin, vimentin, snail, and slug was detected by western blot. Immunofluorescence was also used to detect E-cadherin expression. Western blot was used to determine the level of phosphorylated-inhibitor of kappa B (IκB)a, inhibitor of gamma B (IγB)a, and nuclear factor kappa B (NF-κB) expressions and to explore the ILK signaling pathway.RESULTS: Western blot results revealed that ILK expression significantly increased when ILK was overexpressed in SW480 cells (P < 0.05). Proliferation, metastasis, and invasion ability were improved in the vector-ILK group compared to the vector group (P < 0.05). Immunofluorescence results revealed that E-cadherin fluorescence intensity decreased after ILK was overexpressed (P < 0.05). Western blot results revealed that the protein expression of E-cadherin was reduced, while vimentin, snail, and slug were upregulated when ILK was overexpressed in SW480 cells (P < 0.05). In order to determine the role of the NF-κB signaling pathway in ILK overexpression promoted EMT occurrence, we overexpressed ILK in SW480 cells and found that levels of NF-κB/p65 and cytoplasmic phosphorylated-IκBa were increased and that cytoplasmic IкBa levels were decreased compared to the control group (P < 0.05). Furthermore, NF-κB/p65 knockout revealed that E-cadherin was increased in the overexpressed ILK group.CONCLUSION: ILK overexpression improved the proliferation, metastasis, and invasion ability of SW480 cells, and this effect may be mediated by the NF-κB signaling pathway.展开更多
A nonlocal strain gradient theory(NSGT) accounts for not only the nongradient nonlocal elastic stress but also the nonlocality of higher-order strain gradients,which makes it benefit from both hardening and softening ...A nonlocal strain gradient theory(NSGT) accounts for not only the nongradient nonlocal elastic stress but also the nonlocality of higher-order strain gradients,which makes it benefit from both hardening and softening effects in small-scale structures.In this study, based on the NSGT, an analytical model for the vibration behavior of a piezoelectric sandwich nanobeam is developed with consideration of flexoelectricity. The sandwich nanobeam consists of two piezoelectric sheets and a non-piezoelectric core. The governing equation of vibration of the sandwich beam is obtained by the Hamiltonian principle. The natural vibration frequency of the nanobeam is calculated for the simply supported(SS) boundary, the clamped-clamped(CC) boundary, the clamped-free(CF)boundary, and the clamped-simply supported(CS) boundary. The effects of geometric dimensions, length scale parameters, nonlocal parameters, piezoelectric constants, as well as the flexoelectric constants are discussed. The results demonstrate that both the flexoelectric and piezoelectric constants enhance the vibration frequency of the nanobeam.The nonlocal stress decreases the natural vibration frequency, while the strain gradient increases the natural vibration frequency. The natural vibration frequency based on the NSGT can be increased or decreased, depending on the value of the nonlocal parameter to length scale parameter ratio.展开更多
Researches and applications of Geographic Information Systems (GIS) in China started in the early 1980s. In the early period, the development of GIS was mainly depended on the progress and applications of remote sensi...Researches and applications of Geographic Information Systems (GIS) in China started in the early 1980s. In the early period, the development of GIS was mainly depended on the progress and applications of remote sensing, aerial photography, as well as computer aided design (CAD). In recent years, with the development of Global Positioning System(GPS) and Internet technology, GIS has being developed vigorously in the county. Looking ahead to the 21st century, a new era of “Digital Earth” and “Cyberspace” is coming, which will provide a great opportunity as well as a challenge to the China’s GIS circles.展开更多
Objective To assess the relationship between murine recurrent spontaneous abortion and lymphocyte infiltration at the fetomaternal interface Materials&Methods Hysterolaparotomy was performed on d13.5 of murine ges...Objective To assess the relationship between murine recurrent spontaneous abortion and lymphocyte infiltration at the fetomaternal interface Materials&Methods Hysterolaparotomy was performed on d13.5 of murine gestation,and resorption rate of embryos was calculated in two different mating combinations of abortion model CBA/J×DBA/2 and of the fertile control CBA/J×BALB/c,respectively.CD69 was used as an activation marker on NK cell surface,while DX5 was used as a common marker of NK cell in this study.The proportions of CD 69^(+)cells in isolated lymphocytes,and CD 69^(+)DX 5^(+)cells in DX5^(+)subpopulation at the fetomaternal interface were determined by two-color flow cytometry.It was further evaluated whether there was linear correlation between these cell proportions and resorption rate of embryos.Results Resorption rate of embryos were 36.0%and 7.2%(P<0.01)in CBA/J×DBA/2 and CBA/J×BALB/c(genotypes are all of H-2^(k)×H-2^(d)),respectively.In CBA/J×DBA/2 mice,no linear correlation was observed between the proportion of CD69^(+)cells in lymphocytes(x)and resorption rate(y)(r=0.4054).However,it appeared that the proportion of CD69^(+)DX 5^(+)cells/DX5^(+)cells(x)was strongly linear correlated with the resorption rate of embryos(y)(r=0.8156,y=-0.3958+2.1237x)in this model.Conclusion Infiltration of CD 69^(+)DX5^(+)cells at the fetomaternal interface may be associated with recurrent embryo-resorption in CBA/J×DBA/2 mice.展开更多
Objective： To investigate the recurrent patterns and factors involved in node-negative advanced gastric cancer after curative resection. Patients and Methods： Clinicopathological characteristics and prognostic outco...Objective： To investigate the recurrent patterns and factors involved in node-negative advanced gastric cancer after curative resection. Patients and Methods： Clinicopathological characteristics and prognostic outcomes of 310 patients who had lymph node-negative advanced gastric adenocarcinoma and received curative resection between 2002 and 2006 were retrospectively evaluated. Results： Among the 300 patients, 15 （5.0%） had locoregional recurrence, 5 （1.7%） had lymph node recurrence, 27 （9.0%） had peritoneal seeding recurrence, and 21 （7.0%） had hematogenous metastasis. Using multivariate analysis, we found that the maximum tumor diameter （P=0.014）, histological type （P=0.001） and Borrmann type （P=0.033） were independent factors predicting the locoregional recurrence. Lymph node recurrence was significantly affected by lymph node dissection （P=0.029） and lymphovascular invasion （P=0.004）. Clinicopathological factors predicting the peritoneal seeding recurrence were the depth of invasion （P=0.001） and Borrmann type （P=0.002）. In addition, lymphovascular invasion （P=0.013） and histological type （P=0.001） were significantly associated with hematogenous metastasis. Conclusion： Node-negative advanced gastric cancer has a high amount of peritoneal seeding and hematogenous metastasis.展开更多
Objective:To investigate the association of body mass index(BMI),waist circumference(WC),and waist-to-height ratio(WHtR)with the long-term prognosis of ST-elevation myocardial infarction(STEMI)patients and to determin...Objective:To investigate the association of body mass index(BMI),waist circumference(WC),and waist-to-height ratio(WHtR)with the long-term prognosis of ST-elevation myocardial infarction(STEMI)patients and to determine whether the combination of obesity indices can be used for risk stratification.Method:A multifactorial Cox regression analysis was performed using 3-year follow-up data from 220 STEMI patients to explore the relationship between obesity indicators and major adverse cardiovascular events(MACEs).The incidence of MACEs was also compared by combining BMI and WHtR.Results:WC was found to reduce the risk of MACEs within 25 months after myocardial infarction[hazard ratio(HR)=0.95,95%confidence interval(CI)=0.92-0.98,P<0.001].However,this effect was not significant beyond 25 months(HR=0.98,95%CI=0.97-1.07,P=0.49).Neither BMI nor WHtR were significantly associated with the risk of MACEs.The incidence of MACEs was highest in patients with low body weight(BMI<18.5 kg/m^(2))and WHtR>0.5,and lowest in obese patients(BMI≥28 kg/m^(2))with WHtR>0.5.Conclusions:BMI,WC,and WHtR were not significantly associated with the long-term prognosis of STEMI patients.However,the combination of BMI and WHtR can be useful for further stratifying patient risk.展开更多
Background Neonatal hyperbilirubinemia risk factors determination is challenging due to the lack of quantifiable indicators for bilirubin production,resulting in phototherapy decisions made without real-time informati...Background Neonatal hyperbilirubinemia risk factors determination is challenging due to the lack of quantifiable indicators for bilirubin production,resulting in phototherapy decisions made without real-time information.End-tidal carbon monoxide(CO)corrected for ambient CO(ETCOc)may be helpful for identifying hemolysis,but evidence on the application of ETCOc as a risk factor for the development of neonatal hyperbilirubinemia is scarce.This study aimed to evaluate whether the use of ETCOc to adjust neonatal hyperbilirubinemia risk categories and thus phototherapy thresholds can reduce the rate of phototherapy within the first seven days of life.Methods This is a randomized clinical trial including near-term and term infants with a transcutaneous bilirubin>40th percentile within 72 hours after birth in a single center in Guangdong,China.Newborns were randomized to receive ETCOcadjusted risk assessment or empirical assessment per local practice to establish phototherapy thresholds.The primary outcome was the rate of phototherapy within seven days of life.Secondary outcomes were postnatal hours at phototherapy,total serum bilirubin and ETCOc before phototherapy,severe hyperbilirubinemia and phototherapy duration.Results A total of 2500 infants were enrolled and randomized.Phototherapy within seven days of life occurred in 237 infants(18.9%)in the intervention group and 281 infants(22.5%)in the control group[adjusted relative risk:0.85;95%confidence interval(CI):0.73,0.98].The ETCOc before phototherapy was 0.28 parts per million higher(95%CI:0.10,0.46)in the intervention group.The rate of subsequent severe hyperbilirubinemia was not significantly different,and other secondary outcomes were comparable between the two groups.Conclusions For near-term and term infants at risk of neonatal hyperbilirubinemia,the use of ETCOc to adjust neonatal hyperbilirubinemia risk categories can decrease the rate of phototherapy at seven days of life.Integrating the ETCOc to adjust the phototherapy threshold is helpful in the management of severe hyperbilirubinemia.展开更多
This paper presents an energy resolution study of the JUNO experiment,incorporating the latest knowledge acquired during the detector construction phase.The determination of neutrino mass ordering in JUNO requires an ...This paper presents an energy resolution study of the JUNO experiment,incorporating the latest knowledge acquired during the detector construction phase.The determination of neutrino mass ordering in JUNO requires an exceptional energy resolution better than 3% at 1 MeV.To achieve this ambitious goal,significant efforts have been undertaken in the design and production of the key components of the JUNO detector.Various factors affecting the detection of inverse beta decay signals have an impact on the energy resolution,extending beyond the statistical fluctuations of the detected number of photons,such as the properties of the liquid scintillator,performance of photomultiplier tubes,and the energy reconstruction algorithm.To account for these effects,a full JUNO simulation and reconstruction approach is employed.This enables the modeling of all relevant effects and the evaluation of associated inputs to accurately estimate the energy resolution.The results of this study reveal an energy resolution of 2.95% at 1 Mev.Furthermore,this study assesses the contribution of major effects to the overall energy resolution budget.This analysis serves as a reference for interpreting future measurements of energy resolution during JUNO data collection.Moreover,it provides a guideline for comprehending the energy resolution characteristics of liquid scintillator-based detectors.展开更多
T follicular helper(Tfh)cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation,which are crucial in humoral immune responses.However,aberrant control of Tfh cells also...T follicular helper(Tfh)cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation,which are crucial in humoral immune responses.However,aberrant control of Tfh cells also contributes to the generation of self-reactive autoantibodies and promotes autoimmune diseases such as systemic lupus erythematosus(SLE).The mechanisms that control proper Tfh expansion remain unclear.Here,we show that farnesoid X receptor(FXR)is relatively upregulated in Tfh cells.Genetic deletion of Fxr restrains Tfh expansion both at steady state and in pristane-induced lupus.As a consequence of these defects,mice lacking Fxr manifested GC dysfunction and decreased plasma cell and autoantibody production,which alleviated nephritis progression in pristane-induced lupus.Mechanistically,FXR intrinsically regulates cholesterol homeostasis in Tfh cells,which subsequently controls Tfh cell proliferation.Preclinical treatment of wild-type(WT)mice with the clinically approved drug ursodeoxycholic acid(UDCA)to reduce FXR signaling mitigated lupus disease progression by repressing Tfh expansion,the GC reaction and autoantibody production.These findings provide a rationale for exploring FXR as a potential therapeutic target for SLE.展开更多
The Jiangmen Underground Neutrino Observatory(JUNO)is a multi-purpose neutrino experiment under construction in South China.This paper presents an updated estimate of JUNO’s sensitivity to neutrino mass ordering usin...The Jiangmen Underground Neutrino Observatory(JUNO)is a multi-purpose neutrino experiment under construction in South China.This paper presents an updated estimate of JUNO’s sensitivity to neutrino mass ordering using the reactor antineutrinos emitted from eight nuclear reactor cores in the Taishan and Yangjiang nuclear power plants.This measurement is planned by studying the fine interference pattern caused by quasi-vacuum oscillations in the oscillated antineutrino spectrum at a baseline of 52.5 km and is completely independent of the CP violating phase and neutrino mixing angleθ_(23).The sensitivity is obtained through a joint analysis of JUNO and Taishan Antineutrino Observatory(TAO)detectors utilizing the best available knowledge to date about the location and overburden of the JUNO experimental site,local and global nuclear reactors,JUNO and TAO detector responses,expected event rates and spectra of signals and backgrounds,and systematic uncertainties of analysis inputs.We find that a 3σmedian sensitivity to reject the wrong mass ordering hypothesis can be reached with an exposure of about 6.5 years×26.6 GW thermal power.展开更多
The instability of the motion layer of fertilizer particle influences the precision and the accuracy of the amount of fertilizer application in the working process of fluted-roller fertilizer applicator.The characteri...The instability of the motion layer of fertilizer particle influences the precision and the accuracy of the amount of fertilizer application in the working process of fluted-roller fertilizer applicator.The characteristics of the motion layer were investigated,and a systematic scheme was proposed for designing the structures of fertilizer-filling cavity,fertilizer-filling surface and fertilizer-delivery cavity.The key parameters of the structure were studied by discrete element method.It was figured out that to ensure the smooth operation of fertilizer applicator,the fertilizer-filling angle was 105°,fertilizer-contact angle should be large than 100°,and the fertilizer-resistance angle should be smaller than 35°.Moreover,the stability of fertilizer motion morphology was investigated to verify the design.The results showed that when the roll rotational speed was larger than 120 deg/s,compared with the conventional design the CV of the amount of fertilizer application was reduced from 1.5%-3.5%to 0.5%-1.0%,and the accuracy of the fertilizer discharge was improved with the square of the correlation coefficient between the amount of fertilizer application and the roll rotational speed was larger than 0.999.It was deduced from the results that the precision and accuracy of the amount of fertilizer application are improved via eliminating the driving layer and enhancing the stable filling and conveying of the forced layer.展开更多
Significant developments in cancer treatment have been made since the advent of immune therapies.However,there are still some patientswithmalignant tumors who do not benefit from immunotherapy.Tumors without immunogen...Significant developments in cancer treatment have been made since the advent of immune therapies.However,there are still some patientswithmalignant tumors who do not benefit from immunotherapy.Tumors without immunogenicity are called“cold”tumors which are unresponsive to immunotherapy,and the opposite are“hot”tumors.Immune suppressive cells(ISCs)refer to cells which can inhibit the immune response such as tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),regulatory T(Treg)cells and so on.The more ISCs infiltrated,the weaker the immunogenicity of the tumor,showing the characteristics of“cold”tumor.The dysfunction of ISCs in the tumor microenvironment(TME)may play essential roles in insensitive therapeutic reaction.Previous studies have found that epigeneticmechanisms play an important role in the regulation of ISCs.Regulating ISCs may be a new approach to transforming“cold”tumors into“hot”tumors.Here,we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs.In addition,we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in“cold”tumor.展开更多
In the traditional fertilization method,a large amount of fertilizer is applied,which causes congestion easily.It is not conducive to the sustainable development of agriculture.In this work,a vertical pneumatic fertil...In the traditional fertilization method,a large amount of fertilizer is applied,which causes congestion easily.It is not conducive to the sustainable development of agriculture.In this work,a vertical pneumatic fertilization system with a spiral Geneva mechanism was designed according to the operational requirements of variable-rate and smooth fertilization.The uniformity in discharging fertilizer with different spiral angles was simulated and analyzed by extended discrete element method(EDEM)based simulation software,from where the spiral angle of the fertilizer discharge wheel was determined to be 45°.The fertilization system includes a fertilizer apparatus with a spiral Geneva mechanism,whose optimal performance parameters were obtained from the bench experiment.The accuracy and uniformity of the fertilizer application system were taken as the evaluation indicators.The linear relationships of the discharged amount of fertilizer with the rotational speed and the opening of the fertilizer discharging wheel were verified by both static blowing fertilization and field experiments.The static blowing experimental results show that the discharged amount of fertilizer has a high linear correlation and accuracy with both the opening and rotational speed,and the highest correlation occurs with the rotational speed.The rotational speed and opening have significant effects on the discharged amount of fertilizer and the average coefficient of variation.The effect of the rotational speed was the most significant.According to the model obtained by multiple regression fittings,the optimal parameters were determined when the average coefficient of variation was small,the rotational speed was 15.9 r/min and the opening was 34.4 mm.Therefore,the purpose of precise fertilization can be achieved by adjusting the opening or rotational speed in a way to get the exact amount of fertilizer discharged as required by the corresponding crops.The field experiment showed that the variation coefficient of each fertilizer discharged decreases first and then increases with an increasing opening under different rotational speeds,which is consistent with the theoretical value.When the opening was 40 mm or 50 mm,the variation coefficient reached the minimum value,which is far less than the qualified index of 7.8%.In the static blowing experiment and the dynamic field experiment,the stability of the fertilizer discharging device can be significantly enhanced with the utilization of the pneumatic conveying fertilizer.This study can provide a theoretical reference for parameter selection and optimization of vertical spiral fertilization systems.展开更多
The mixtures,grains,and residues in the ratooning rice harvesting machine need to be conveyed forward,backward,upward,and downward.Due to such operations,often accumulation and blockage take place at the intersection ...The mixtures,grains,and residues in the ratooning rice harvesting machine need to be conveyed forward,backward,upward,and downward.Due to such operations,often accumulation and blockage take place at the intersection of a horizontal-vertical screw conveyor,resulting in low efficiency,high power consumption,and even grain damage.In this study,a CFD-DEM approach was applied to address the above problems.Firstly,a pneumatic conveying device was designed for ratooning rice,and then the motion of the rice grains and airflow field was analyzed in detail.The effects of different cross-sectional heights and lengths of the contraction section related to the mixing cavity were examined.Finally,the three-factor quadratic regression orthogonal rotational combination method was adopted in the experiment,and the fan velocity,filling coefficient,and speed of the horizontal screw conveyor were taken as test factors.The results showed that with the increasing cross-sectional height of the contraction section in the mixing cavity,the grain velocity decreased and the dispersity increased.With increasing length of the contraction section in the mixing cavity,the area of the high-speed airflow zone increased and the diffusion effect was enhanced.At the fan velocity of 2700 r/min,the filling coefficient was 0.41,the speed of the horizontal screw conveyor was 1173 r/min,and the outlet flow optimization index was the highest,which was 45.9%higher than that obtained without airflow.展开更多
Objective:Real-world diagnostic and treatment data for pancreatic cancer in China are lacking.As such,the present study investigated the clinical characteristics,diagnosis,and treatment of advanced pancreatic cancer(i...Objective:Real-world diagnostic and treatment data for pancreatic cancer in China are lacking.As such,the present study investigated the clinical characteristics,diagnosis,and treatment of advanced pancreatic cancer(including locally advanced and metastatic disease)in the Hospital-based Advanced Pancreatic Cancer Cohort in China of the China Pancreas Data Center database.Methods:A total of 5349 Chinese patients with advanced pancreatic cancer were identified from a database.The entire course of real-world pancreatic cancer management was analyzed.Results:The proportion of patients with advanced pancreatic cancer was higher among males than females(62.4%vs 37.6%,respectively).Patients typically had a history of hypertension(30.8%),diabetes(21.6%),and cholangitis(20.2%).Abdominal pain(51.6%),abdominal distension(27.1%),jaundice(20.1%),and weight loss(16.3%)were the main symptoms observed in patients with advanced pancreatic cancer in this cohort.Serum carbohydrate antigen(CA)19-9 is one of the most common tumor markers.In the present study,2562 patients underwent first-line therapy.The median progression-free survival(PFS)for patients undergoing first-line therapy was 4.1 months.The major options for first-line therapy included gemcitabine(GEM)plus S-1(GS/X)(23.4%),nab-paclitaxel plus GEM(AG)(18.1%),oxaliplatin,irinotecan,and leucovorin-modulated fluorouracil(FOLFIRINOX;11.9%),nab-paclitaxel plus S-1(AS)(8.9%),and GEM combined with oxaliplatin/cisplatin(GEMOX/GP)(7.6%).The AS and GS/X regimens were associated with the highest PFS rates.Conclusion:This is the first study to report multicenter,real-world data regarding advanced pancreatic cancer in China.Results revealed that real-world treatment options differed from guideline recommendations,and PFS was shorter than that in previously reported data.Improving intelligent follow-up systems and standardizing diagnosis and treatment of pancreatic cancer is recommended.展开更多
Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship be...Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.展开更多
基金the National Nature Science Foundation of China,Nos.30770971,30800518,81070362,81172470 and 81372629two key projects from the Nature Science Foundation of Hunan Province,Nos.11JJ2049 and 12JJ3118
文摘Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.
基金Supported by the National Natural Science Foundation of China(Beijing,China,grant No’s.30770971,81172470,81070362 and 81372629)
文摘AIM: To investigate the effect of integrin-linked kinase (ILK) on proliferation, metastasis, and invasion of the colorectal cancer cell line SW480.METHODS: In this study, the colorectal cancer cell line SW480 was stably transfected with ILK plasmids, and small interfering RNA (siRNA) was used to knockdown expression of nuclear factor (NF)-κB/p65. Methylthiazole tetrazolium (MTT) assay was performed to measure proliferation, and the wound healing migration assay and matrigel invasion assay were used to test the metastasis and invasion ability of SW480 cells. To explore the epithelial-mesenchymal transition (EMT) process, embryonic development, and the invasion and metastasis of tumors, the protein level of E-cadherin, vimentin, snail, and slug was detected by western blot. Immunofluorescence was also used to detect E-cadherin expression. Western blot was used to determine the level of phosphorylated-inhibitor of kappa B (IκB)a, inhibitor of gamma B (IγB)a, and nuclear factor kappa B (NF-κB) expressions and to explore the ILK signaling pathway.RESULTS: Western blot results revealed that ILK expression significantly increased when ILK was overexpressed in SW480 cells (P < 0.05). Proliferation, metastasis, and invasion ability were improved in the vector-ILK group compared to the vector group (P < 0.05). Immunofluorescence results revealed that E-cadherin fluorescence intensity decreased after ILK was overexpressed (P < 0.05). Western blot results revealed that the protein expression of E-cadherin was reduced, while vimentin, snail, and slug were upregulated when ILK was overexpressed in SW480 cells (P < 0.05). In order to determine the role of the NF-κB signaling pathway in ILK overexpression promoted EMT occurrence, we overexpressed ILK in SW480 cells and found that levels of NF-κB/p65 and cytoplasmic phosphorylated-IκBa were increased and that cytoplasmic IкBa levels were decreased compared to the control group (P < 0.05). Furthermore, NF-κB/p65 knockout revealed that E-cadherin was increased in the overexpressed ILK group.CONCLUSION: ILK overexpression improved the proliferation, metastasis, and invasion ability of SW480 cells, and this effect may be mediated by the NF-κB signaling pathway.
基金Project supported by the National Natural Science Foundation of China(Nos.51965041,1197237,11602072)。
文摘A nonlocal strain gradient theory(NSGT) accounts for not only the nongradient nonlocal elastic stress but also the nonlocality of higher-order strain gradients,which makes it benefit from both hardening and softening effects in small-scale structures.In this study, based on the NSGT, an analytical model for the vibration behavior of a piezoelectric sandwich nanobeam is developed with consideration of flexoelectricity. The sandwich nanobeam consists of two piezoelectric sheets and a non-piezoelectric core. The governing equation of vibration of the sandwich beam is obtained by the Hamiltonian principle. The natural vibration frequency of the nanobeam is calculated for the simply supported(SS) boundary, the clamped-clamped(CC) boundary, the clamped-free(CF)boundary, and the clamped-simply supported(CS) boundary. The effects of geometric dimensions, length scale parameters, nonlocal parameters, piezoelectric constants, as well as the flexoelectric constants are discussed. The results demonstrate that both the flexoelectric and piezoelectric constants enhance the vibration frequency of the nanobeam.The nonlocal stress decreases the natural vibration frequency, while the strain gradient increases the natural vibration frequency. The natural vibration frequency based on the NSGT can be increased or decreased, depending on the value of the nonlocal parameter to length scale parameter ratio.
文摘Researches and applications of Geographic Information Systems (GIS) in China started in the early 1980s. In the early period, the development of GIS was mainly depended on the progress and applications of remote sensing, aerial photography, as well as computer aided design (CAD). In recent years, with the development of Global Positioning System(GPS) and Internet technology, GIS has being developed vigorously in the county. Looking ahead to the 21st century, a new era of “Digital Earth” and “Cyberspace” is coming, which will provide a great opportunity as well as a challenge to the China’s GIS circles.
基金Supported by the National Key Fundamental Research Plan("973")Projet(G1999050303)Major Project of Science and Technology Guangzhou Province(A302020204)China
文摘Objective To assess the relationship between murine recurrent spontaneous abortion and lymphocyte infiltration at the fetomaternal interface Materials&Methods Hysterolaparotomy was performed on d13.5 of murine gestation,and resorption rate of embryos was calculated in two different mating combinations of abortion model CBA/J×DBA/2 and of the fertile control CBA/J×BALB/c,respectively.CD69 was used as an activation marker on NK cell surface,while DX5 was used as a common marker of NK cell in this study.The proportions of CD 69^(+)cells in isolated lymphocytes,and CD 69^(+)DX 5^(+)cells in DX5^(+)subpopulation at the fetomaternal interface were determined by two-color flow cytometry.It was further evaluated whether there was linear correlation between these cell proportions and resorption rate of embryos.Results Resorption rate of embryos were 36.0%and 7.2%(P<0.01)in CBA/J×DBA/2 and CBA/J×BALB/c(genotypes are all of H-2^(k)×H-2^(d)),respectively.In CBA/J×DBA/2 mice,no linear correlation was observed between the proportion of CD69^(+)cells in lymphocytes(x)and resorption rate(y)(r=0.4054).However,it appeared that the proportion of CD69^(+)DX 5^(+)cells/DX5^(+)cells(x)was strongly linear correlated with the resorption rate of embryos(y)(r=0.8156,y=-0.3958+2.1237x)in this model.Conclusion Infiltration of CD 69^(+)DX5^(+)cells at the fetomaternal interface may be associated with recurrent embryo-resorption in CBA/J×DBA/2 mice.
文摘Objective： To investigate the recurrent patterns and factors involved in node-negative advanced gastric cancer after curative resection. Patients and Methods： Clinicopathological characteristics and prognostic outcomes of 310 patients who had lymph node-negative advanced gastric adenocarcinoma and received curative resection between 2002 and 2006 were retrospectively evaluated. Results： Among the 300 patients, 15 （5.0%） had locoregional recurrence, 5 （1.7%） had lymph node recurrence, 27 （9.0%） had peritoneal seeding recurrence, and 21 （7.0%） had hematogenous metastasis. Using multivariate analysis, we found that the maximum tumor diameter （P=0.014）, histological type （P=0.001） and Borrmann type （P=0.033） were independent factors predicting the locoregional recurrence. Lymph node recurrence was significantly affected by lymph node dissection （P=0.029） and lymphovascular invasion （P=0.004）. Clinicopathological factors predicting the peritoneal seeding recurrence were the depth of invasion （P=0.001） and Borrmann type （P=0.002）. In addition, lymphovascular invasion （P=0.013） and histological type （P=0.001） were significantly associated with hematogenous metastasis. Conclusion： Node-negative advanced gastric cancer has a high amount of peritoneal seeding and hematogenous metastasis.
基金National Natural Science Foundation of China(Grant/Award Number:81970304)Tianjin Municipal Science and Technology Commission(Grant/Award Numbers:18ZXZNSY00290 and 19JCQNJC11500).
文摘Objective:To investigate the association of body mass index(BMI),waist circumference(WC),and waist-to-height ratio(WHtR)with the long-term prognosis of ST-elevation myocardial infarction(STEMI)patients and to determine whether the combination of obesity indices can be used for risk stratification.Method:A multifactorial Cox regression analysis was performed using 3-year follow-up data from 220 STEMI patients to explore the relationship between obesity indicators and major adverse cardiovascular events(MACEs).The incidence of MACEs was also compared by combining BMI and WHtR.Results:WC was found to reduce the risk of MACEs within 25 months after myocardial infarction[hazard ratio(HR)=0.95,95%confidence interval(CI)=0.92-0.98,P<0.001].However,this effect was not significant beyond 25 months(HR=0.98,95%CI=0.97-1.07,P=0.49).Neither BMI nor WHtR were significantly associated with the risk of MACEs.The incidence of MACEs was highest in patients with low body weight(BMI<18.5 kg/m^(2))and WHtR>0.5,and lowest in obese patients(BMI≥28 kg/m^(2))with WHtR>0.5.Conclusions:BMI,WC,and WHtR were not significantly associated with the long-term prognosis of STEMI patients.However,the combination of BMI and WHtR can be useful for further stratifying patient risk.
基金supported by the grant of“Plan on Enhancing Scientific research in Guangzhou Medical University(GMU)”(No.GMUCR2024-01014)supported by the Research Foundation of Guangzhou Women and Children’s Medical Center for Clinical Doctor(No.2021BS035)+2 种基金the Postdoctoral Fellowship Grant of China Postdoctoral Science Foundation(Grant No.2022M720892)the Basic and Applied Basic ScienceProject and Municipal-University-Enterprise Joint Sponsorship Project of the Guangzhou Science and Technology Bureau(No.2023A03J0882,2023A04J1223)the Young Science and Technology Talent Support Program of Guangdong Precision Medicine Application Association(No.YSTTGDPMAA202502)。
文摘Background Neonatal hyperbilirubinemia risk factors determination is challenging due to the lack of quantifiable indicators for bilirubin production,resulting in phototherapy decisions made without real-time information.End-tidal carbon monoxide(CO)corrected for ambient CO(ETCOc)may be helpful for identifying hemolysis,but evidence on the application of ETCOc as a risk factor for the development of neonatal hyperbilirubinemia is scarce.This study aimed to evaluate whether the use of ETCOc to adjust neonatal hyperbilirubinemia risk categories and thus phototherapy thresholds can reduce the rate of phototherapy within the first seven days of life.Methods This is a randomized clinical trial including near-term and term infants with a transcutaneous bilirubin>40th percentile within 72 hours after birth in a single center in Guangdong,China.Newborns were randomized to receive ETCOcadjusted risk assessment or empirical assessment per local practice to establish phototherapy thresholds.The primary outcome was the rate of phototherapy within seven days of life.Secondary outcomes were postnatal hours at phototherapy,total serum bilirubin and ETCOc before phototherapy,severe hyperbilirubinemia and phototherapy duration.Results A total of 2500 infants were enrolled and randomized.Phototherapy within seven days of life occurred in 237 infants(18.9%)in the intervention group and 281 infants(22.5%)in the control group[adjusted relative risk:0.85;95%confidence interval(CI):0.73,0.98].The ETCOc before phototherapy was 0.28 parts per million higher(95%CI:0.10,0.46)in the intervention group.The rate of subsequent severe hyperbilirubinemia was not significantly different,and other secondary outcomes were comparable between the two groups.Conclusions For near-term and term infants at risk of neonatal hyperbilirubinemia,the use of ETCOc to adjust neonatal hyperbilirubinemia risk categories can decrease the rate of phototherapy at seven days of life.Integrating the ETCOc to adjust the phototherapy threshold is helpful in the management of severe hyperbilirubinemia.
基金Supported by the Chinese Academy of Sciencesthe National Key R&D Program of China+20 种基金the CAS Center for Excellence in Particle Physics,Wuyi Universitythe Tsung-Dao Lee Institute of Shanghai Jiao Tong University in Chinathe Institut National de Physique Nucléaire et de Physique de Particules(IN2P3)in Francethe Istituto Nazionale di Fisica Nucleare(INFN)in Italythe Italian-Chinese collaborative research program MAECI-NSFCthe Fond de la Recherche Scientifique(F.R.S-FNRS)FWO under the"Excellence of Science-EOS"in Belgiumthe Conselho Nacional de Desenvolvimento Científico e Tecnològico in Brazilthe Agencia Nacional de Investigacion y Desarrollo and ANID Millennium Science Initiative Program—ICN2019_044 in Chilethe Charles University Research Centre and the Ministry of Education,Youth,and Sports in Czech Republicthe Deutsche Forschungsgemeinschaft(DFG)the Helmholtz Associationthe Cluster of Excellence PRISMA+in Germanythe Joint Institute of Nuclear Research(JINR)Lomonosov Moscow State University in Russiathe joint Russian Science Foundation(RSF)National Natural Science Foundation of China(NSFC)research programthe MOST and MOE in Taiwan,Chinathe Chulalongkorn University and Suranaree University of Technology in Thailandthe University of California at Irvinethe National Science Foundation in USA。
文摘This paper presents an energy resolution study of the JUNO experiment,incorporating the latest knowledge acquired during the detector construction phase.The determination of neutrino mass ordering in JUNO requires an exceptional energy resolution better than 3% at 1 MeV.To achieve this ambitious goal,significant efforts have been undertaken in the design and production of the key components of the JUNO detector.Various factors affecting the detection of inverse beta decay signals have an impact on the energy resolution,extending beyond the statistical fluctuations of the detected number of photons,such as the properties of the liquid scintillator,performance of photomultiplier tubes,and the energy reconstruction algorithm.To account for these effects,a full JUNO simulation and reconstruction approach is employed.This enables the modeling of all relevant effects and the evaluation of associated inputs to accurately estimate the energy resolution.The results of this study reveal an energy resolution of 2.95% at 1 Mev.Furthermore,this study assesses the contribution of major effects to the overall energy resolution budget.This analysis serves as a reference for interpreting future measurements of energy resolution during JUNO data collection.Moreover,it provides a guideline for comprehending the energy resolution characteristics of liquid scintillator-based detectors.
基金supported by the National Natural Science Foundation of China(82271866,82471853 and 82402127)the Guangzhou Key Research and Development Program(02A004999000186)the Guangdong Basic and Applied Basic Research Foundation(2024B1515020039,2021A1515011451,2017B030314120 and 202201011028).
文摘T follicular helper(Tfh)cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation,which are crucial in humoral immune responses.However,aberrant control of Tfh cells also contributes to the generation of self-reactive autoantibodies and promotes autoimmune diseases such as systemic lupus erythematosus(SLE).The mechanisms that control proper Tfh expansion remain unclear.Here,we show that farnesoid X receptor(FXR)is relatively upregulated in Tfh cells.Genetic deletion of Fxr restrains Tfh expansion both at steady state and in pristane-induced lupus.As a consequence of these defects,mice lacking Fxr manifested GC dysfunction and decreased plasma cell and autoantibody production,which alleviated nephritis progression in pristane-induced lupus.Mechanistically,FXR intrinsically regulates cholesterol homeostasis in Tfh cells,which subsequently controls Tfh cell proliferation.Preclinical treatment of wild-type(WT)mice with the clinically approved drug ursodeoxycholic acid(UDCA)to reduce FXR signaling mitigated lupus disease progression by repressing Tfh expansion,the GC reaction and autoantibody production.These findings provide a rationale for exploring FXR as a potential therapeutic target for SLE.
基金Supported by the Chinese Academy of Sciences,the National Key R&D Program of Chinathe CAS Center for Excellence in Particle Physics,Wuyi University,and the TsungDao Lee Institute of Shanghai Jiao Tong University in China+3 种基金the Institut National de Physique Nucléaire et de Physique de Particules(IN2P3)in Francethe Istituto Nazionale di Fisica Nucleare(INFN)in Italy,the Italian-Chinese collaborative research program MAECI-NSFC,the Fond de la Recherche Scientifique(F.R.S-FNRS)and FWO under the“Excellence of Science–EOS”in Belgium,the Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnol`ogico in Brazil,the Agencia Nacional de Investigacion y Desarrollo and ANID-Millennium Science Initiative Program-ICN2019_044 in Chilethe Charles University Research Centre and the Ministry of Education,Youth,and Sports in Czech Republic,the Deutsche Forschungsgemeinschaft(DFG)the Helmholtz Association,and the Cluster of Excellence PRISMA+in Germany,the Joint Institute of Nuclear Research(JINR)and Lomonosov Moscow State University in Russia,the joint Russian Science Foundation(RSF)and National Natural Science Foundation of China(NSFC)research program,the MOST and MOE in Taiwan,China,the Chulalongkorn University and Suranaree University of Technology in Thailand,University of California at Irvine and the National Science Foundation in the US。
文摘The Jiangmen Underground Neutrino Observatory(JUNO)is a multi-purpose neutrino experiment under construction in South China.This paper presents an updated estimate of JUNO’s sensitivity to neutrino mass ordering using the reactor antineutrinos emitted from eight nuclear reactor cores in the Taishan and Yangjiang nuclear power plants.This measurement is planned by studying the fine interference pattern caused by quasi-vacuum oscillations in the oscillated antineutrino spectrum at a baseline of 52.5 km and is completely independent of the CP violating phase and neutrino mixing angleθ_(23).The sensitivity is obtained through a joint analysis of JUNO and Taishan Antineutrino Observatory(TAO)detectors utilizing the best available knowledge to date about the location and overburden of the JUNO experimental site,local and global nuclear reactors,JUNO and TAO detector responses,expected event rates and spectra of signals and backgrounds,and systematic uncertainties of analysis inputs.We find that a 3σmedian sensitivity to reject the wrong mass ordering hypothesis can be reached with an exposure of about 6.5 years×26.6 GW thermal power.
基金We acknowledge that this research was financially supported by National Key Research Program Project(No.2016YFD0200600,2016YFD0200606,2018YFD0200700,2018YFD0200704,2017YFD0700500,2017YFD0700503).
文摘The instability of the motion layer of fertilizer particle influences the precision and the accuracy of the amount of fertilizer application in the working process of fluted-roller fertilizer applicator.The characteristics of the motion layer were investigated,and a systematic scheme was proposed for designing the structures of fertilizer-filling cavity,fertilizer-filling surface and fertilizer-delivery cavity.The key parameters of the structure were studied by discrete element method.It was figured out that to ensure the smooth operation of fertilizer applicator,the fertilizer-filling angle was 105°,fertilizer-contact angle should be large than 100°,and the fertilizer-resistance angle should be smaller than 35°.Moreover,the stability of fertilizer motion morphology was investigated to verify the design.The results showed that when the roll rotational speed was larger than 120 deg/s,compared with the conventional design the CV of the amount of fertilizer application was reduced from 1.5%-3.5%to 0.5%-1.0%,and the accuracy of the fertilizer discharge was improved with the square of the correlation coefficient between the amount of fertilizer application and the roll rotational speed was larger than 0.999.It was deduced from the results that the precision and accuracy of the amount of fertilizer application are improved via eliminating the driving layer and enhancing the stable filling and conveying of the forced layer.
基金National Natural Science Foundation of China,Grant/Award Numbers:82373275,81974384,82173342,82203015China Postdoctoral Science Foundation,Grant/Award Number:2023JJ40942+3 种基金Nature Science Foundation of Hunan Province,Grant/Award Numbers:2021JJ3109,2021JJ31048,2023JJ40942Nature Science Foundation of Changsha,Grant/Award Number:73201CSCO Cancer Research Foundation,Grant/Award Numbers:Y-HR2019-0182,Y-2019Genecast-043the Key Research and Development Program of Hainan Province,Grant/Award Numbers:ZDYF2020228,ZDYF2020125。
文摘Significant developments in cancer treatment have been made since the advent of immune therapies.However,there are still some patientswithmalignant tumors who do not benefit from immunotherapy.Tumors without immunogenicity are called“cold”tumors which are unresponsive to immunotherapy,and the opposite are“hot”tumors.Immune suppressive cells(ISCs)refer to cells which can inhibit the immune response such as tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),regulatory T(Treg)cells and so on.The more ISCs infiltrated,the weaker the immunogenicity of the tumor,showing the characteristics of“cold”tumor.The dysfunction of ISCs in the tumor microenvironment(TME)may play essential roles in insensitive therapeutic reaction.Previous studies have found that epigeneticmechanisms play an important role in the regulation of ISCs.Regulating ISCs may be a new approach to transforming“cold”tumors into“hot”tumors.Here,we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs.In addition,we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in“cold”tumor.
基金The authors gratefully acknowledge the support was provided by the National Key Research and Development Program of China(Grant No.2017YFD0700700,2017YFD0700704,2016YFD0200600,2016YFD0200606,2018YFD0200700).
文摘In the traditional fertilization method,a large amount of fertilizer is applied,which causes congestion easily.It is not conducive to the sustainable development of agriculture.In this work,a vertical pneumatic fertilization system with a spiral Geneva mechanism was designed according to the operational requirements of variable-rate and smooth fertilization.The uniformity in discharging fertilizer with different spiral angles was simulated and analyzed by extended discrete element method(EDEM)based simulation software,from where the spiral angle of the fertilizer discharge wheel was determined to be 45°.The fertilization system includes a fertilizer apparatus with a spiral Geneva mechanism,whose optimal performance parameters were obtained from the bench experiment.The accuracy and uniformity of the fertilizer application system were taken as the evaluation indicators.The linear relationships of the discharged amount of fertilizer with the rotational speed and the opening of the fertilizer discharging wheel were verified by both static blowing fertilization and field experiments.The static blowing experimental results show that the discharged amount of fertilizer has a high linear correlation and accuracy with both the opening and rotational speed,and the highest correlation occurs with the rotational speed.The rotational speed and opening have significant effects on the discharged amount of fertilizer and the average coefficient of variation.The effect of the rotational speed was the most significant.According to the model obtained by multiple regression fittings,the optimal parameters were determined when the average coefficient of variation was small,the rotational speed was 15.9 r/min and the opening was 34.4 mm.Therefore,the purpose of precise fertilization can be achieved by adjusting the opening or rotational speed in a way to get the exact amount of fertilizer discharged as required by the corresponding crops.The field experiment showed that the variation coefficient of each fertilizer discharged decreases first and then increases with an increasing opening under different rotational speeds,which is consistent with the theoretical value.When the opening was 40 mm or 50 mm,the variation coefficient reached the minimum value,which is far less than the qualified index of 7.8%.In the static blowing experiment and the dynamic field experiment,the stability of the fertilizer discharging device can be significantly enhanced with the utilization of the pneumatic conveying fertilizer.This study can provide a theoretical reference for parameter selection and optimization of vertical spiral fertilization systems.
文摘The mixtures,grains,and residues in the ratooning rice harvesting machine need to be conveyed forward,backward,upward,and downward.Due to such operations,often accumulation and blockage take place at the intersection of a horizontal-vertical screw conveyor,resulting in low efficiency,high power consumption,and even grain damage.In this study,a CFD-DEM approach was applied to address the above problems.Firstly,a pneumatic conveying device was designed for ratooning rice,and then the motion of the rice grains and airflow field was analyzed in detail.The effects of different cross-sectional heights and lengths of the contraction section related to the mixing cavity were examined.Finally,the three-factor quadratic regression orthogonal rotational combination method was adopted in the experiment,and the fan velocity,filling coefficient,and speed of the horizontal screw conveyor were taken as test factors.The results showed that with the increasing cross-sectional height of the contraction section in the mixing cavity,the grain velocity decreased and the dispersity increased.With increasing length of the contraction section in the mixing cavity,the area of the high-speed airflow zone increased and the diffusion effect was enhanced.At the fan velocity of 2700 r/min,the filling coefficient was 0.41,the speed of the horizontal screw conveyor was 1173 r/min,and the outlet flow optimization index was the highest,which was 45.9%higher than that obtained without airflow.
基金funded by the National Natural Science Foundation of China(Grant nos.81874048,82171824,82272906)Shanghai Municipal Commission of Health and Family Planning Grant 2018ZHYL0223+6 种基金Shanghai Municipal Education Commission—Gao Feng Clinical Medicine Grant Support(Grant no.20161312)Scientific and Technological Innovation Project of Science and Technology Commission of Shanghai Municipality(Grant no.21JC1404300)Clinical Research Plan of SHDC(Grant no.SHDC2020CR1035B)Innovation Group Project of Shanghai Municipal Health Commission(Grant no.2019CXJQ03)National Key R&D Program of China(Grant no.2019YFC1315900)Project from CSCO Clinical Oncology Research Foundation(Grant no.Y-2019AZZD-0513)the Innovative Research Team of High-Level Local Universities in Shanghai(Grant no.SHSMU-ZDCX20210802).
文摘Objective:Real-world diagnostic and treatment data for pancreatic cancer in China are lacking.As such,the present study investigated the clinical characteristics,diagnosis,and treatment of advanced pancreatic cancer(including locally advanced and metastatic disease)in the Hospital-based Advanced Pancreatic Cancer Cohort in China of the China Pancreas Data Center database.Methods:A total of 5349 Chinese patients with advanced pancreatic cancer were identified from a database.The entire course of real-world pancreatic cancer management was analyzed.Results:The proportion of patients with advanced pancreatic cancer was higher among males than females(62.4%vs 37.6%,respectively).Patients typically had a history of hypertension(30.8%),diabetes(21.6%),and cholangitis(20.2%).Abdominal pain(51.6%),abdominal distension(27.1%),jaundice(20.1%),and weight loss(16.3%)were the main symptoms observed in patients with advanced pancreatic cancer in this cohort.Serum carbohydrate antigen(CA)19-9 is one of the most common tumor markers.In the present study,2562 patients underwent first-line therapy.The median progression-free survival(PFS)for patients undergoing first-line therapy was 4.1 months.The major options for first-line therapy included gemcitabine(GEM)plus S-1(GS/X)(23.4%),nab-paclitaxel plus GEM(AG)(18.1%),oxaliplatin,irinotecan,and leucovorin-modulated fluorouracil(FOLFIRINOX;11.9%),nab-paclitaxel plus S-1(AS)(8.9%),and GEM combined with oxaliplatin/cisplatin(GEMOX/GP)(7.6%).The AS and GS/X regimens were associated with the highest PFS rates.Conclusion:This is the first study to report multicenter,real-world data regarding advanced pancreatic cancer in China.Results revealed that real-world treatment options differed from guideline recommendations,and PFS was shorter than that in previously reported data.Improving intelligent follow-up systems and standardizing diagnosis and treatment of pancreatic cancer is recommended.
基金This work was supported by the National Key R&D Program of China(No.2017YFA0103900)the National Natural Science Foundation of China(Nos.81771011,81771010,81700910,81700914,and 81400463)+2 种基金the Development Fund for Shanghai Talents(No.2017046)the Excellent Personnel Training Plan for Shanghai Health System(No.2017Q003)the Shanghai HFPC Foundation(No.201440402).
文摘Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.
