Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to...Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.展开更多
The increasing performance demands of modern aero engines necessitate the integrated design of compressor transition ducts with upstream components to reduce the axial length of the engine.However,this design approach...The increasing performance demands of modern aero engines necessitate the integrated design of compressor transition ducts with upstream components to reduce the axial length of the engine.However,this design approach narrows the spacing between the stator and the strut,making traditional research on transition ducts only with struts unsuitable.The numerical results and experimental oil flow visualization results were utilized to reconstruct the three-dimensional flow structures in the stator passages under various operating conditions.Additionally,numerical methods were employed to analyze the mechanisms of the strut's effect on the upstream stator in an aggressive transition duct.The results show that the strut potential field increases the load on the upstream stator,leading to severe blade surface separation and corner separation/stall,and redistributes the inflow angle of the upstream stators circumferentially,resulting in significant differences in the flow structures within the stator passages on both sides.The separation flows within the stator passages mainly manifest in five types:pressure surface separation vortex,suction surface concentrated shedding vortex,suction surface separation vortex,suction surface-corner stall separation vortex,and suction surface separation vortex pair.Under different operating conditions,the separation flows within the stator passages are always composed of a part of these five types or a transitional state between two of them.展开更多
Manufactured blades are inevitably different from their design intent,which leads to a deviation of the performance from the intended value.To quantify the associated performance uncertainty,many approaches have been ...Manufactured blades are inevitably different from their design intent,which leads to a deviation of the performance from the intended value.To quantify the associated performance uncertainty,many approaches have been developed.The traditional Monte Carlo method based on a Computational Fluid Dynamics solver(MC-CFD)for a three-dimensional compressor is prohibitively expensive.Existing alternatives to the MC-CFD,such as surrogate models and secondorder derivatives based on the adjoint method,can greatly reduce the computational cost.Nevertheless,they will encounter’the curse of dimensionality’except for the linear model based on the adjoint gradient(called MC-adj-linear).However,the MC-adj-linear model neglects the nonlinearity of the performance function.In this work,an improved method is proposed to circumvent the lowaccuracy problem of the MC-adj-linear without incurring the high cost of other alternative models.The method is applied to the study of the aerodynamic performance of an annular transonic compressor cascade,subject to prescribed geometric variability with industrial relevance.It is found that the proposed method achieves a significant accuracy improvement over the MC-adj-linear with low computational cost,showing the great potential for fast uncertainty quantification.展开更多
It is confirmed that tandem-blade configurations have potential to enlarge the flow turning in two-dimension(2D) studies. However, the potential of tandem blades to enlarge the design space for highly loaded axial com...It is confirmed that tandem-blade configurations have potential to enlarge the flow turning in two-dimension(2D) studies. However, the potential of tandem blades to enlarge the design space for highly loaded axial compressors was rarely investigated in open literatures. The present work aims to show the capability of tandem blades to break the loading limit of conventional blades for highly loaded compressors. The 2D models of the maximum static pressure rise derived in previous work were validated by a large amount experimental data, which showed a good agreement. An E parameter was defined to evaluate the stall margin of compressor based on the theoretical models, which indicated that the tandem blade was able to increase the loading limit of axial compressors. A single-blade stage with a loading coefficient of 0.46(based on the blade tip rotating speed) was designed as the baseline case under the guidance of the E parameter. A tandem-blade stage was then designed by ensuring that the velocity triangles were similar to the single-blade stage. The performances of both stages were investigated experimentally. The results showed that the maximum efficiency of the tandem-blade stage was 92.8%, 1% higher than the single;the stall margin increased from 16.9% to 22.3%. Besides, the maximum pressure rise of tandem rotors was beyond the loading limit of 2D single-blade cascades, which confirmed the potential of tandem blades to break the loading limit of axial compressors.展开更多
The variable cycle engine is distinguished by its highly adjustable compression system,whose aerodynamic characteristic is extremely complex.To explore the regulation range of a double bypass engine compression system...The variable cycle engine is distinguished by its highly adjustable compression system,whose aerodynamic characteristic is extremely complex.To explore the regulation range of a double bypass engine compression system,a multi-dimensional analysis method is developed,through which the coupling mechanism between the compressor component and the bypass is examined.The operation zones of the compressor components and the bypass system are proposed,and the operation range of the compression system is obtained by calculating the overlapping part of the operation zones.The results show that in the double bypass mode,there exists a minimum mode selector valve area and a minimum core driven fan stage stall margin that ensures a feasible bypass flow,the two parameters correspond to each other.Under the given fan and core driven fan stage conditions,the maximum value of the inner bypass ratio is restricted by the upper limit of the forward variable area bypass injector and the maximum Mach number in the total bypass,while the minimum value of the inner bypass ratio depends on the lower limit of the forward variable area bypass injector geometry and the system recirculation margin.The single bypass mode is a unique condition of the double bypass mode,as the operation zone of the compressor component degenerates from a two-dimensional surface to a straight line.There are multiple bypass states available in the single bypass mode,while the regulation range of the bypass ratio is jointly restricted by the operation range of the high pressure compressor and the aerodynamic boundary of the forward variable area bypass injector.展开更多
In this study,the influence of inter-stage bleeding on the compressor performance and inter-stage flow field of a multistage axial compressor is investigated by both experimental and numerical methods.The experiment i...In this study,the influence of inter-stage bleeding on the compressor performance and inter-stage flow field of a multistage axial compressor is investigated by both experimental and numerical methods.The experiment is conducted on a four-stage low-speed axial compressor,and a specific computational model is built to simulate the experiment environment accurately.To illuminate the fluid mechanisms of bleeding effect in detail,both the experiment and the simulation are carried out twice,i.e.,in the first time,the mass flow rate upstream the bleed location is constant under different bleed rate conditions;while in the second time,the mass flow rate downstream the bleed location is constant under different bleed rate conditions.The results demonstrate that inter-stage bleeding has little influence on upstream compressor characteristics,and affects the upstream flow field only in the rear half of the stator.The bleed effect on the downstream flow field is embodied in the variation of an incoming flow profile,an increase as the compressor inlet flow coefficient decreases.Therefore,such an effect is only significant on compressor characteristics at small flow coefficient conditions.In multistage compressors,the variation of compressor characteristics and flow field caused by inter-stage bleeding is the comprehensive result of the bleeding and the variation of the upstream working condition.In addition,the comparison between numerical and experimental results shows that the flow moves towards top half of span through the downstream rotor passage in the numerical simulation,whereas the trend of flow field variation with different bleed rates at the outlet of the downstream rotor and stator is the same with that at the inlet of the downstream rotor in the experiment,which means that the numerical method has overestimated the radial mixing intensity of the flow.展开更多
Manufacture variations can greatly increase the performance variability of compressor blades. Current robust design optimization methods have a critical role in reducing the adverse impact of the variations, but can b...Manufacture variations can greatly increase the performance variability of compressor blades. Current robust design optimization methods have a critical role in reducing the adverse impact of the variations, but can be affected by errors if the assumptions of the deviation models and distribution parameters are inaccurate. A new approach for robust design optimization without the employment of the deviation models is proposed. The deviation package method and the interval estimation method are exploited in this new approach. Simultaneously, a stratified strategy is used to reduce the computational cost and assure the optimization accuracy. The test case employed for this study is a typical transonic compressor blade profile, which resembles most of the manufacture features of modern compressor blades. A set of 96 newly manufactured blades was measured using a coordinate measurement machine to obtain the manufacture variations and produce a deviation package. The optimization results show that the scatter of the aerodynamic performance for the optimal robust design is 20% less than the baseline value. By comparing the optimization results obtained from the deviation package method with those obtained from widely-used methods employing the deviation model, the efficiency and accuracy of the deviation package method are demonstrated. Finally, the physical mechanisms that control the robustness of different designs were further investigated, and some statistical laws of robust design were extracted.展开更多
Uncertainties in the aerodynamic performance of compressors,introduced by manufacturing variations,have received more and more attentions in recent years.The deviation model plays a crucial role in evaluating this unc...Uncertainties in the aerodynamic performance of compressors,introduced by manufacturing variations,have received more and more attentions in recent years.The deviation model plays a crucial role in evaluating this uncertainty and facilitating robust design.However,current deviation models with a few variables cannot simultaneously achieve a precise geometric approximation of deviation and provide an accurate assessment of performance uncertainty.This paper introduces a novel deviation modeling method named Nested Principal Component Analysis(NPCA)to break this tradeoff.In this method,both geometry-based and performance-based modes are utilized to describe manufacturing variations.By considering aerodynamic sensitivity,surface deformations that significantly impact aerodynamic performance can be extracted for deviation modeling.To demonstrate the superiority of this newly proposed method,ninety-eight newly manufactured compressor rotor blades were measured using a coordinate measurement machine,and both NPCA and Principal Component Analysis(PCA)were employed to model the real manufacturing variations.The results indicate that,in comparison to the PCA method,the NPCA method achieves an equivalent level of accuracy in geometric reconstruction and evaluation of mean performance.Furthermore,the same level of accuracy can be obtained with eight NPCA modes and fifty PCA modes when assessing the scatter in aerodynamic performance.Finally,the working mechanism of the NPCA method for accurate uncertainty quantification was further investigated.展开更多
Particle Image Velocimetry(PIV)is a well-developed and contactless technique in experimental fluid mechanics,but the strong velocity gradient and streamline curvature near the wall substantially limits its accuracy im...Particle Image Velocimetry(PIV)is a well-developed and contactless technique in experimental fluid mechanics,but the strong velocity gradient and streamline curvature near the wall substantially limits its accuracy improvement.This paper presents a data processing procedure combining conventional PIV and newly developed Mirror Interchange(MI)based Interface-PIV for the measurement of the boundary layer parameter development in the blade leading edge region.The synthetic particle images are used to analyze the measurement errors in the entire procedure.Overall,three types of errors,namely the errors caused by the Window Deformation Iterative Multigrid(WIDIM)algorithm,the discrete data interpolation and integration,and the wall offset uncertainty,comprise the main measurement error.Specifically,the errors due to the discrete data interpolation and integration and the WIDIM algorithm comprise the mean bias,which can be corrected through the error analysis method proposed in the present work.Meanwhile,the errors due to the WIDIM algorithm and the wall offset uncertainty contribute to the measurement uncertainty.Computational fluid dynamics-based synthetic particle flows were generated to verify the newly developed PIV data processing procedure and the corresponding error analysis method.Results showed that the data processing method could improve the accuracy of PIV measurements for boundary layer flows with high curvature and acceleration and even with significant flow separation bubbles.Finally,the data processing method is also applied in a PIV experiment to investigate the boundary layer flows around a compressor blade leading edge,and several credible boundary flow parameters were obtained.展开更多
Multiple endocrine neoplasia 1(MEN1)syndrome,a disease arising from a genetic predisposition to tumor development caused by MEN1 loss-of-function mutations,is characterized by the combined occurrence of neuroendocrine...Multiple endocrine neoplasia 1(MEN1)syndrome,a disease arising from a genetic predisposition to tumor development caused by MEN1 loss-of-function mutations,is characterized by the combined occurrence of neuroendocrine tumors in multiple human organs.With advances in diagnostic technologies and improvements in living standards.展开更多
Background: Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair...Background: Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair, has been reported to predict the outcomes of different cancer types. However, the function of SMUG1 in pancreatic cancer is still unclear. Methods: Gene and protein expression of SMUG1 as well as survival outcomes were assessed by bioinformatic analysis and verified in a cohort from Fudan University Shanghai Cancer Center. Subsequently, the effect of SMUG1 on proliferation, cell cycle, and migration abilities of SMUG1 cells were detected in vitro . DNA damage repair, apoptosis, and gemcitabine resistance were also tested. RNA sequencing was performed to determine the differentially expressed genes and signaling pathways, followed by quantitative real-time polymerase chain reaction and Western blotting verification. The cancer-promoting effect of forkhead box Q1 (FOXQ1) and SMUG1 on the ubiquitylation of myelocytomatosis oncogene (c-Myc) was also evaluated. Finally, a xenograft model was established to verify the results. Results: SMUG1 was highly expressed in pancreatic tumor tissues and cells, which also predicted a poor prognosis. Downregulation of SMUG1 inhibited the proliferation, G1 to S transition, migration, and DNA damage repair ability against gemcitabine in pancreatic cancer cells. SMUG1 exerted its function by binding with FOXQ1 to activate the Protein Kinase B (AKT)/p21 and p27 pathway. Moreover, SMUG1 also stabilized the c-Myc protein via AKT signaling in pancreatic cancer cells. Conclusions: SMUG1 promotes proliferation, migration, gemcitabine resistance, and c-Myc protein stability in pancreatic cancer via protein kinase B signaling through binding with FOXQ1. Furthermore, SMUG1 may be a new potential prognostic and gemcitabine resistance predictor in pancreatic ductal adenocarcinoma.展开更多
Nab-paclitaxel plus gemcitabine(AG)is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy.This phase 1b/2 study aimed to evaluate SHR-1701(an anti-...Nab-paclitaxel plus gemcitabine(AG)is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy.This phase 1b/2 study aimed to evaluate SHR-1701(an anti-PD-L1/TGF-βRII fusion protein)plus AG in this population(NCT04624217).In phase 1b part,the recommended dose of SHR-1701 was identified as 30 mg/kg every 3 weeks,when combined with AG.In phase 2 part,the primary endpoint was objective response rate(ORR).As of Mar 31,2023,56 patients were enrolled.Median follow-up was 10.3 months(range,0.2–24.7).ORR was 32.1%(95%CI,20.3–46.0).Median progressive-free survival(PFS)was 5.6 months(95%CI,4.3–6.6),and median overall survival(OS)was 10.3 months(95%CI,8.8–12.3).Treatment-related adverse events of grade≥3 were reported in 27(48.2%)patients,with the most common being decreased neutrophil count.Patients with PD-L1 TPS≥1%showed a higher ORR(66.7%vs.25.0%),as well as extended median PFS(6.3 vs.5.3 months)and median OS(18.8 vs.9.9 months).Additionally,reduction of CA19-9 by at least 80%during treatment and pSMAD2/3 staining intensity of 1+at baseline were potential monitoring tools and predictive biomarkers for better clinical outcomes,respectively.Tumor-specific T-cell infiltration and pancreatic cancer tumor subtypes were associated with anti-tumor response.The interactions within tumor microenvironment were involved disease progression.Overall,first-line SHR-1701 plus AG showed promising anti-tumor activity and controllable safety in advanced or metastatic pancreatic ductal adenocarcinoma,and features of patients more likely to benefit from the combination were drawn.展开更多
As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth fa...As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth factor-β(TGF-β),Hedgehog(Hh),Notch,Wnt,Hippo,nuclear factor kappa-B(NF-κB),Janus kinase(JAK)/signal transducer and activator of transcription(STAT),mitogen-activated protein kinase(MAPK),and phosphoinositide 3-kinase(PI3K)/AKT pathways,as well as transcription factors,including hypoxia-inducible factor(HIF),heat shock transcription factor 1(HSF1),P53,Snail,and Twist,constitute complex regulatory networks in theTMEtomodulate the formation,activation,heterogeneity,metabolic characteristics and malignant phenotype of CAFs.Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics,and this modulation partially depends on the regulation of signaling cascades.The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures(e.g.,NCT01130142 and NCT01064622).Hence,a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.展开更多
Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the ...Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the technical standards for LPD.Objective:The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review:An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy.Statements were produced upon reviewing the literature and assessed by the members of the expert panel.The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019.The Web of Science,Medline,and Cochrane Library and Clinical Trials databases were searched,The search strategy included,but was not limited to,the terms'laparoscopic','pancreaticoduodenectomy,'pancreatoduodenectomy','Whipple's operation',and'minimally invasive surgery'.Reference lists from the included articles were manually checked for any additional studies,which were included when appropriate.Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements.The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan,China.Findings:Twenty-eight international experts from 8 countries constructed the expert panel.Sixteen statements were produced by the members of the expert panel.At least 80%of responders agreed with the majority(80%)of statements.Other than three randomized controlled trials published to date,most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance:The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD.LPD is currently in its development and exploration stages,as defined by the international IDEAL framework for surgical innovation.More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.展开更多
Over decades,researchers have focused on the epigenetic control of DNA-templated processes.Histone modification,DNA methylation,chromatin remodeling,RNA modification,and noncoding RNAs modulate many biological process...Over decades,researchers have focused on the epigenetic control of DNA-templated processes.Histone modification,DNA methylation,chromatin remodeling,RNA modification,and noncoding RNAs modulate many biological processes that are crucial to the development of cancers.Dysregulation of the epigenome drives aberrant transcriptional programs.A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment.Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses.Thus,the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment.Here,we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment(TME)and how epigenetics influence immune cells internally to modify the TME.Additionally,we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy.Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits.The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME,so that better cancer immunotherapies can be developed.展开更多
Background:The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial,and more high-level clinical evidence is needed.This study aimed to evaluate the outcome of extended pancreatoduodenectom...Background:The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial,and more high-level clinical evidence is needed.This study aimed to evaluate the outcome of extended pancreatoduodenectomy(EPD)with retroperitoneal nerve resection in pancreatic head cancer.Methods:This multicenter randomized trial was performed at 6 Chinese highvolume hospitals that enrolled patients between October 3,2012,and September 21,2017.Four hundred patients with stage I or II pancreatic head cancer and without specific pancreatic cancer treatments(preoperative chemotherapy or chemoradiation)within three months were randomly assigned to undergo standard pancreatoduodenectomy(SPD)or EPD,with the latter followed by dissection of additional lymph nodes(LNs),nerves and soft tissues 270◦on the right side surrounding the superior mesenteric artery and celiac axis.The primary endpoint was overall survival(OS)by intention-to-treat(ITT).The secondary endpoints were disease-free survival(DFS),mortality,morbidity,and postoperative pain intensity.Results:TheR1 ratewas slightly lower with EPD(8.46%)thanwith SPD(12.56%).The morbidity and mortality rates were similar between the two groups.The median OS was similar in the EPD and SPD groups by ITT in the whole study cohort(23.0 vs.20.2 months,P=0.100),while the median DFS was superior in the EPD group(16.1 vs.13.2 months,P=0.031).Patients with preoperative CA19–9<200.0 U/mL had significantly improved OS and DFS with EPD(EPD vs.SPD,30.8 vs.20.9 months,P=0.009;23.4 vs.13.5 months,P<0.001).The EPD group exhibited significantly lower locoregional(16.48%vs.35.20%,P<0.001)andmesenteric LNrecurrence rates(3.98%vs.10.06%,P=0.022).The EPD group exhibited less back pain 6 months postoperation than the SPD group.Conclusions:EPD for pancreatic head cancer did not significantly improve OS,but patients with EPD treatment had significantly improved DFS.In the subgroup analysis,improvements in bothOS and DFS in the EPD armwere observed in patients with preoperative CA19–9<200.0 U/mL.EPD could be used as an effective surgical procedure for patients with pancreatic head cancer,especially those with preoperative CA19–9<200.0 U/mL.展开更多
Liquid–liquid phase separation(LLPS)is a novel principle for explaining the precise spatial and temporal regulation in living cells.LLPS compartmentalizes proteins and nucleic acids into micron-scale,liquid-like,memb...Liquid–liquid phase separation(LLPS)is a novel principle for explaining the precise spatial and temporal regulation in living cells.LLPS compartmentalizes proteins and nucleic acids into micron-scale,liquid-like,membraneless bodies with specific functions,which were recently termed biomolecular condensates.Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities,including chromatin organization,genomic stability,DNA damage response and repair,transcription,and signal transduction.Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer,and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology.In this review,we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS.In addition,we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.展开更多
Acute pancreatitis(AP)is a common acute abdominal condition of the digestive system.In recent years,treatment concepts,methods,and strategies for the diagnosis of AP have advanced,and this has played an important role...Acute pancreatitis(AP)is a common acute abdominal condition of the digestive system.In recent years,treatment concepts,methods,and strategies for the diagnosis of AP have advanced,and this has played an important role in promoting the standardization of AP diagnosis and treatment and improving the treatment quality of AP patients.On the basis of previous guidelines and expert consensus,this guideline adopts an evidence-based,problem-based expression;synthesizes important clinical research data at home and abroad in the most recent 5 years;and forms 29 recommendations through multidisciplinary expert discussion,including diagnosis,treatment,and follow-up.It is expected to provide evidence support for the treatment of AP in the clinical setting in China.展开更多
基金supported by the Projects of International Cooperation and Exchanges(Nos.G2022027004L,G2022027012L)the Hubei Province Natural Science Foundation of China(No.2022CFB481)+3 种基金the Natural Science Foundation of Hubei Provincial Department of Education(No.T2022021)the Advantages Discipline Group(Biology and Medicine)Project in Higher Education of Hubei Province(2021-2025)(Nos.2025BMXKQY2,2024XKQY26)the Innovative Research Program for Graduates of Hubei University of Medicine(No.YC2024003,YC2022033)the Student's Platform for Innovation and Entrepreneurship Training Program(Nos.202410929010,202210929005)。
文摘Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.
基金supported by the National Natural Science Foundation of China(No.52276025)the Science Center for Gas Turbine Project of China(Nos.P2022-A-Ⅱ-001-001,P2022-A-Ⅱ-002-001 and P2022-B-Ⅱ-002-001)。
文摘The increasing performance demands of modern aero engines necessitate the integrated design of compressor transition ducts with upstream components to reduce the axial length of the engine.However,this design approach narrows the spacing between the stator and the strut,making traditional research on transition ducts only with struts unsuitable.The numerical results and experimental oil flow visualization results were utilized to reconstruct the three-dimensional flow structures in the stator passages under various operating conditions.Additionally,numerical methods were employed to analyze the mechanisms of the strut's effect on the upstream stator in an aggressive transition duct.The results show that the strut potential field increases the load on the upstream stator,leading to severe blade surface separation and corner separation/stall,and redistributes the inflow angle of the upstream stators circumferentially,resulting in significant differences in the flow structures within the stator passages on both sides.The separation flows within the stator passages mainly manifest in five types:pressure surface separation vortex,suction surface concentrated shedding vortex,suction surface separation vortex,suction surface-corner stall separation vortex,and suction surface separation vortex pair.Under different operating conditions,the separation flows within the stator passages are always composed of a part of these five types or a transitional state between two of them.
基金funded by the National Natural Science Foundation of China(No.52006177)National Science and Technology Major Project,China(No.2017-II-0009-0023)。
文摘Manufactured blades are inevitably different from their design intent,which leads to a deviation of the performance from the intended value.To quantify the associated performance uncertainty,many approaches have been developed.The traditional Monte Carlo method based on a Computational Fluid Dynamics solver(MC-CFD)for a three-dimensional compressor is prohibitively expensive.Existing alternatives to the MC-CFD,such as surrogate models and secondorder derivatives based on the adjoint method,can greatly reduce the computational cost.Nevertheless,they will encounter’the curse of dimensionality’except for the linear model based on the adjoint gradient(called MC-adj-linear).However,the MC-adj-linear model neglects the nonlinearity of the performance function.In this work,an improved method is proposed to circumvent the lowaccuracy problem of the MC-adj-linear without incurring the high cost of other alternative models.The method is applied to the study of the aerodynamic performance of an annular transonic compressor cascade,subject to prescribed geometric variability with industrial relevance.It is found that the proposed method achieves a significant accuracy improvement over the MC-adj-linear with low computational cost,showing the great potential for fast uncertainty quantification.
基金the support of National Natural Science Foundation of China(Nos.51806004 and 51790511)National Science and Technology Major Project,China(No.2017-Ⅱ-0001-0013)。
文摘It is confirmed that tandem-blade configurations have potential to enlarge the flow turning in two-dimension(2D) studies. However, the potential of tandem blades to enlarge the design space for highly loaded axial compressors was rarely investigated in open literatures. The present work aims to show the capability of tandem blades to break the loading limit of conventional blades for highly loaded compressors. The 2D models of the maximum static pressure rise derived in previous work were validated by a large amount experimental data, which showed a good agreement. An E parameter was defined to evaluate the stall margin of compressor based on the theoretical models, which indicated that the tandem blade was able to increase the loading limit of axial compressors. A single-blade stage with a loading coefficient of 0.46(based on the blade tip rotating speed) was designed as the baseline case under the guidance of the E parameter. A tandem-blade stage was then designed by ensuring that the velocity triangles were similar to the single-blade stage. The performances of both stages were investigated experimentally. The results showed that the maximum efficiency of the tandem-blade stage was 92.8%, 1% higher than the single;the stall margin increased from 16.9% to 22.3%. Besides, the maximum pressure rise of tandem rotors was beyond the loading limit of 2D single-blade cascades, which confirmed the potential of tandem blades to break the loading limit of axial compressors.
基金co-supported by the National Natural Science Foundation of China(No.52206038)the National Science and Technology Major Project,China(No.Y2022-Ⅱ-0003)the Science Center for Gas Turbine Project,China(Nos.P2022-A-Ⅱ-001-001 and P2022-B-Ⅱ-002-001).
文摘The variable cycle engine is distinguished by its highly adjustable compression system,whose aerodynamic characteristic is extremely complex.To explore the regulation range of a double bypass engine compression system,a multi-dimensional analysis method is developed,through which the coupling mechanism between the compressor component and the bypass is examined.The operation zones of the compressor components and the bypass system are proposed,and the operation range of the compression system is obtained by calculating the overlapping part of the operation zones.The results show that in the double bypass mode,there exists a minimum mode selector valve area and a minimum core driven fan stage stall margin that ensures a feasible bypass flow,the two parameters correspond to each other.Under the given fan and core driven fan stage conditions,the maximum value of the inner bypass ratio is restricted by the upper limit of the forward variable area bypass injector and the maximum Mach number in the total bypass,while the minimum value of the inner bypass ratio depends on the lower limit of the forward variable area bypass injector geometry and the system recirculation margin.The single bypass mode is a unique condition of the double bypass mode,as the operation zone of the compressor component degenerates from a two-dimensional surface to a straight line.There are multiple bypass states available in the single bypass mode,while the regulation range of the bypass ratio is jointly restricted by the operation range of the high pressure compressor and the aerodynamic boundary of the forward variable area bypass injector.
基金the support of the National Natural Science Foundation of China(Nos.51806004,51790511)the National Science and Technology Major Project,China(No.2017-Ⅱ-0001-0013)。
文摘In this study,the influence of inter-stage bleeding on the compressor performance and inter-stage flow field of a multistage axial compressor is investigated by both experimental and numerical methods.The experiment is conducted on a four-stage low-speed axial compressor,and a specific computational model is built to simulate the experiment environment accurately.To illuminate the fluid mechanisms of bleeding effect in detail,both the experiment and the simulation are carried out twice,i.e.,in the first time,the mass flow rate upstream the bleed location is constant under different bleed rate conditions;while in the second time,the mass flow rate downstream the bleed location is constant under different bleed rate conditions.The results demonstrate that inter-stage bleeding has little influence on upstream compressor characteristics,and affects the upstream flow field only in the rear half of the stator.The bleed effect on the downstream flow field is embodied in the variation of an incoming flow profile,an increase as the compressor inlet flow coefficient decreases.Therefore,such an effect is only significant on compressor characteristics at small flow coefficient conditions.In multistage compressors,the variation of compressor characteristics and flow field caused by inter-stage bleeding is the comprehensive result of the bleeding and the variation of the upstream working condition.In addition,the comparison between numerical and experimental results shows that the flow moves towards top half of span through the downstream rotor passage in the numerical simulation,whereas the trend of flow field variation with different bleed rates at the outlet of the downstream rotor and stator is the same with that at the inlet of the downstream rotor in the experiment,which means that the numerical method has overestimated the radial mixing intensity of the flow.
基金funded by the National Science and Technology Major Project, China (No. 2017-II-0001-0013)Science Center for Gas Turbine Project, China (Nos. P2022-A-II-002-001 and P2022-B-II-002-001)。
文摘Manufacture variations can greatly increase the performance variability of compressor blades. Current robust design optimization methods have a critical role in reducing the adverse impact of the variations, but can be affected by errors if the assumptions of the deviation models and distribution parameters are inaccurate. A new approach for robust design optimization without the employment of the deviation models is proposed. The deviation package method and the interval estimation method are exploited in this new approach. Simultaneously, a stratified strategy is used to reduce the computational cost and assure the optimization accuracy. The test case employed for this study is a typical transonic compressor blade profile, which resembles most of the manufacture features of modern compressor blades. A set of 96 newly manufactured blades was measured using a coordinate measurement machine to obtain the manufacture variations and produce a deviation package. The optimization results show that the scatter of the aerodynamic performance for the optimal robust design is 20% less than the baseline value. By comparing the optimization results obtained from the deviation package method with those obtained from widely-used methods employing the deviation model, the efficiency and accuracy of the deviation package method are demonstrated. Finally, the physical mechanisms that control the robustness of different designs were further investigated, and some statistical laws of robust design were extracted.
基金funded by the Science Center for Gas Turbine Project,China(Nos.P2022-A-II-002-001,P2022-B-II-002-001)the National Natural Science Foundation of China(No.52206038)
文摘Uncertainties in the aerodynamic performance of compressors,introduced by manufacturing variations,have received more and more attentions in recent years.The deviation model plays a crucial role in evaluating this uncertainty and facilitating robust design.However,current deviation models with a few variables cannot simultaneously achieve a precise geometric approximation of deviation and provide an accurate assessment of performance uncertainty.This paper introduces a novel deviation modeling method named Nested Principal Component Analysis(NPCA)to break this tradeoff.In this method,both geometry-based and performance-based modes are utilized to describe manufacturing variations.By considering aerodynamic sensitivity,surface deformations that significantly impact aerodynamic performance can be extracted for deviation modeling.To demonstrate the superiority of this newly proposed method,ninety-eight newly manufactured compressor rotor blades were measured using a coordinate measurement machine,and both NPCA and Principal Component Analysis(PCA)were employed to model the real manufacturing variations.The results indicate that,in comparison to the PCA method,the NPCA method achieves an equivalent level of accuracy in geometric reconstruction and evaluation of mean performance.Furthermore,the same level of accuracy can be obtained with eight NPCA modes and fifty PCA modes when assessing the scatter in aerodynamic performance.Finally,the working mechanism of the NPCA method for accurate uncertainty quantification was further investigated.
基金funded by the National Natural Science Foundation of China(Nos.51790511 and 51806004)the National Science and Technology Major Project,China(No.2017-II-0001-0013).
文摘Particle Image Velocimetry(PIV)is a well-developed and contactless technique in experimental fluid mechanics,but the strong velocity gradient and streamline curvature near the wall substantially limits its accuracy improvement.This paper presents a data processing procedure combining conventional PIV and newly developed Mirror Interchange(MI)based Interface-PIV for the measurement of the boundary layer parameter development in the blade leading edge region.The synthetic particle images are used to analyze the measurement errors in the entire procedure.Overall,three types of errors,namely the errors caused by the Window Deformation Iterative Multigrid(WIDIM)algorithm,the discrete data interpolation and integration,and the wall offset uncertainty,comprise the main measurement error.Specifically,the errors due to the discrete data interpolation and integration and the WIDIM algorithm comprise the mean bias,which can be corrected through the error analysis method proposed in the present work.Meanwhile,the errors due to the WIDIM algorithm and the wall offset uncertainty contribute to the measurement uncertainty.Computational fluid dynamics-based synthetic particle flows were generated to verify the newly developed PIV data processing procedure and the corresponding error analysis method.Results showed that the data processing method could improve the accuracy of PIV measurements for boundary layer flows with high curvature and acceleration and even with significant flow separation bubbles.Finally,the data processing method is also applied in a PIV experiment to investigate the boundary layer flows around a compressor blade leading edge,and several credible boundary flow parameters were obtained.
基金jointly supported by the National Natural Science Foundation of China(Grant No.U21A20374),National Natural Science Foundation of China(Grant Nos.82141129 and 82141104)Shanghai Municipal Science and Technology Major Project(Grant No.21JC1401500)+4 种基金Scientific Innovation Project of Shanghai Education Committee(Grant No.2019-01-0700-07-E00057)Clinical Research Plan of Shanghai Hospital Development Center(Grant No.SHDC2020CR1006A)Xuhui District Artificial Intelligence Medical Hospital Cooperation Project(Grant No.2021-011)Shanghai Municipal Science and Technology Commission(Grant No.19QA1402100)Shanghai Pujiang Program(Grant No.22PJ1401800).
文摘Multiple endocrine neoplasia 1(MEN1)syndrome,a disease arising from a genetic predisposition to tumor development caused by MEN1 loss-of-function mutations,is characterized by the combined occurrence of neuroendocrine tumors in multiple human organs.With advances in diagnostic technologies and improvements in living standards.
基金funded by the National Natural Science Foundation of China(Nos.81802352,82072698,and U21A20374)the Shanghai Municipal Science and Technology Major Project(No.21JC1401500)+4 种基金the Shanghai Rising-Star Program(No.20QA1402100)the Clinical and Scientific Innovation Project of the Shanghai Hospital Development Center(Nos.SHDC12018109 and SHDC12019109)the Clinical Research Plan of the Shanghai Hospital Development Center(No.SHDC2020CR1006A)the Scientific Innovation Project of the Shanghai Education Committee(No.2019-01-07-00-07-E00057)the Xuhui District Artificial Intelligence Medical Hospital Cooperation Project(No.2021-011).
文摘Background: Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair, has been reported to predict the outcomes of different cancer types. However, the function of SMUG1 in pancreatic cancer is still unclear. Methods: Gene and protein expression of SMUG1 as well as survival outcomes were assessed by bioinformatic analysis and verified in a cohort from Fudan University Shanghai Cancer Center. Subsequently, the effect of SMUG1 on proliferation, cell cycle, and migration abilities of SMUG1 cells were detected in vitro . DNA damage repair, apoptosis, and gemcitabine resistance were also tested. RNA sequencing was performed to determine the differentially expressed genes and signaling pathways, followed by quantitative real-time polymerase chain reaction and Western blotting verification. The cancer-promoting effect of forkhead box Q1 (FOXQ1) and SMUG1 on the ubiquitylation of myelocytomatosis oncogene (c-Myc) was also evaluated. Finally, a xenograft model was established to verify the results. Results: SMUG1 was highly expressed in pancreatic tumor tissues and cells, which also predicted a poor prognosis. Downregulation of SMUG1 inhibited the proliferation, G1 to S transition, migration, and DNA damage repair ability against gemcitabine in pancreatic cancer cells. SMUG1 exerted its function by binding with FOXQ1 to activate the Protein Kinase B (AKT)/p21 and p27 pathway. Moreover, SMUG1 also stabilized the c-Myc protein via AKT signaling in pancreatic cancer cells. Conclusions: SMUG1 promotes proliferation, migration, gemcitabine resistance, and c-Myc protein stability in pancreatic cancer via protein kinase B signaling through binding with FOXQ1. Furthermore, SMUG1 may be a new potential prognostic and gemcitabine resistance predictor in pancreatic ductal adenocarcinoma.
文摘Nab-paclitaxel plus gemcitabine(AG)is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy.This phase 1b/2 study aimed to evaluate SHR-1701(an anti-PD-L1/TGF-βRII fusion protein)plus AG in this population(NCT04624217).In phase 1b part,the recommended dose of SHR-1701 was identified as 30 mg/kg every 3 weeks,when combined with AG.In phase 2 part,the primary endpoint was objective response rate(ORR).As of Mar 31,2023,56 patients were enrolled.Median follow-up was 10.3 months(range,0.2–24.7).ORR was 32.1%(95%CI,20.3–46.0).Median progressive-free survival(PFS)was 5.6 months(95%CI,4.3–6.6),and median overall survival(OS)was 10.3 months(95%CI,8.8–12.3).Treatment-related adverse events of grade≥3 were reported in 27(48.2%)patients,with the most common being decreased neutrophil count.Patients with PD-L1 TPS≥1%showed a higher ORR(66.7%vs.25.0%),as well as extended median PFS(6.3 vs.5.3 months)and median OS(18.8 vs.9.9 months).Additionally,reduction of CA19-9 by at least 80%during treatment and pSMAD2/3 staining intensity of 1+at baseline were potential monitoring tools and predictive biomarkers for better clinical outcomes,respectively.Tumor-specific T-cell infiltration and pancreatic cancer tumor subtypes were associated with anti-tumor response.The interactions within tumor microenvironment were involved disease progression.Overall,first-line SHR-1701 plus AG showed promising anti-tumor activity and controllable safety in advanced or metastatic pancreatic ductal adenocarcinoma,and features of patients more likely to benefit from the combination were drawn.
基金National Natural Science Foundation of China,Grant/Award Numbers:81802352,82002541,81772555,81902428National Science Foundation for Distinguished Young Scholars of China,Grant/Award Number:81625016+4 种基金Shanghai Sailing Program,Grant/Award Number:20YF1409000Shanghai Rising-Star Program,Grant/Award Number:20QA1402100Shanghai Anticancer Association Young Eagle Program,Grant/Award Number:SACA-CY19A06Clinical and Scientific Innovation Project of Shanghai Hospital Development Center,Grant/Award Numbers:SHDC12018109,SHDC12019109Scientific Innovation Project of Shanghai Education Committee,Grant/Award Number:2019-01-07-00-07-E00057。
文摘As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth factor-β(TGF-β),Hedgehog(Hh),Notch,Wnt,Hippo,nuclear factor kappa-B(NF-κB),Janus kinase(JAK)/signal transducer and activator of transcription(STAT),mitogen-activated protein kinase(MAPK),and phosphoinositide 3-kinase(PI3K)/AKT pathways,as well as transcription factors,including hypoxia-inducible factor(HIF),heat shock transcription factor 1(HSF1),P53,Snail,and Twist,constitute complex regulatory networks in theTMEtomodulate the formation,activation,heterogeneity,metabolic characteristics and malignant phenotype of CAFs.Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics,and this modulation partially depends on the regulation of signaling cascades.The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures(e.g.,NCT01130142 and NCT01064622).Hence,a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.
基金This study was supported by grants from The National Natural Science Foundation of China(81772950)Tongji Hospital Clinical Research Flagship Program(2019CR203)to RQ.
文摘Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the technical standards for LPD.Objective:The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review:An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy.Statements were produced upon reviewing the literature and assessed by the members of the expert panel.The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019.The Web of Science,Medline,and Cochrane Library and Clinical Trials databases were searched,The search strategy included,but was not limited to,the terms'laparoscopic','pancreaticoduodenectomy,'pancreatoduodenectomy','Whipple's operation',and'minimally invasive surgery'.Reference lists from the included articles were manually checked for any additional studies,which were included when appropriate.Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements.The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan,China.Findings:Twenty-eight international experts from 8 countries constructed the expert panel.Sixteen statements were produced by the members of the expert panel.At least 80%of responders agreed with the majority(80%)of statements.Other than three randomized controlled trials published to date,most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance:The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD.LPD is currently in its development and exploration stages,as defined by the international IDEAL framework for surgical innovation.More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.
基金supported by the National Natural Science Foundation of China(U21A20374,82072698)Shanghai Rising-Star Program(no.20QA1402100)+3 种基金Shanghai Municipal Science and Technology Major Project(21JC1401500)Scientific Innovation Project of Shanghai Education Committee(2019-01-07-00-07-E00057)Clinical Research Plan of Shanghai Hospital Developmen Center(SHDC2020CR1006A)Xuhui District Artificial Intelligence Medical Hospital Cooperation Project(2021-011).
文摘Over decades,researchers have focused on the epigenetic control of DNA-templated processes.Histone modification,DNA methylation,chromatin remodeling,RNA modification,and noncoding RNAs modulate many biological processes that are crucial to the development of cancers.Dysregulation of the epigenome drives aberrant transcriptional programs.A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment.Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses.Thus,the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment.Here,we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment(TME)and how epigenetics influence immune cells internally to modify the TME.Additionally,we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy.Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits.The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME,so that better cancer immunotherapies can be developed.
基金Sun Yat-sen University Clinical Research 5010 Program,Grant/Award Number:2012007National Natural Science Foundation of China,Grant/Award Number:81871945National Key Clinical Specialty Construction Project,Grant/Award Number:2022YW030009。
文摘Background:The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial,and more high-level clinical evidence is needed.This study aimed to evaluate the outcome of extended pancreatoduodenectomy(EPD)with retroperitoneal nerve resection in pancreatic head cancer.Methods:This multicenter randomized trial was performed at 6 Chinese highvolume hospitals that enrolled patients between October 3,2012,and September 21,2017.Four hundred patients with stage I or II pancreatic head cancer and without specific pancreatic cancer treatments(preoperative chemotherapy or chemoradiation)within three months were randomly assigned to undergo standard pancreatoduodenectomy(SPD)or EPD,with the latter followed by dissection of additional lymph nodes(LNs),nerves and soft tissues 270◦on the right side surrounding the superior mesenteric artery and celiac axis.The primary endpoint was overall survival(OS)by intention-to-treat(ITT).The secondary endpoints were disease-free survival(DFS),mortality,morbidity,and postoperative pain intensity.Results:TheR1 ratewas slightly lower with EPD(8.46%)thanwith SPD(12.56%).The morbidity and mortality rates were similar between the two groups.The median OS was similar in the EPD and SPD groups by ITT in the whole study cohort(23.0 vs.20.2 months,P=0.100),while the median DFS was superior in the EPD group(16.1 vs.13.2 months,P=0.031).Patients with preoperative CA19–9<200.0 U/mL had significantly improved OS and DFS with EPD(EPD vs.SPD,30.8 vs.20.9 months,P=0.009;23.4 vs.13.5 months,P<0.001).The EPD group exhibited significantly lower locoregional(16.48%vs.35.20%,P<0.001)andmesenteric LNrecurrence rates(3.98%vs.10.06%,P=0.022).The EPD group exhibited less back pain 6 months postoperation than the SPD group.Conclusions:EPD for pancreatic head cancer did not significantly improve OS,but patients with EPD treatment had significantly improved DFS.In the subgroup analysis,improvements in bothOS and DFS in the EPD armwere observed in patients with preoperative CA19–9<200.0 U/mL.EPD could be used as an effective surgical procedure for patients with pancreatic head cancer,especially those with preoperative CA19–9<200.0 U/mL.
基金study was jointly supported by the National Natural Science Foundation of China(U21A20374 and 82072698)Shanghai Municipal Science and Technology Major Project(21JC1401500)+2 种基金Scientific Innovation Project of Shanghai Education Committee(2019-01-07-00-07-E00057)Clinical Research Plan of Shanghai Hospital Development Center(SHDC2020CR1006A)Xuhui District Artificial Intelligence Medical Hospital Cooperation Project(2021-011).
文摘Liquid–liquid phase separation(LLPS)is a novel principle for explaining the precise spatial and temporal regulation in living cells.LLPS compartmentalizes proteins and nucleic acids into micron-scale,liquid-like,membraneless bodies with specific functions,which were recently termed biomolecular condensates.Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities,including chromatin organization,genomic stability,DNA damage response and repair,transcription,and signal transduction.Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer,and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology.In this review,we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS.In addition,we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.
文摘Acute pancreatitis(AP)is a common acute abdominal condition of the digestive system.In recent years,treatment concepts,methods,and strategies for the diagnosis of AP have advanced,and this has played an important role in promoting the standardization of AP diagnosis and treatment and improving the treatment quality of AP patients.On the basis of previous guidelines and expert consensus,this guideline adopts an evidence-based,problem-based expression;synthesizes important clinical research data at home and abroad in the most recent 5 years;and forms 29 recommendations through multidisciplinary expert discussion,including diagnosis,treatment,and follow-up.It is expected to provide evidence support for the treatment of AP in the clinical setting in China.
