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| 1 | 帕博利珠单抗单用或与放疗联用治疗转移性非小细胞肺癌:两个随机试验的汇总分析显示文摘背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,联合疗法组显示出潜在获益。由于每个研究的样本量较小,缓解率和结局并未显示出统计学意义,然而却有显著的临床获益。因此,本研究进行汇总分析,来判断放疗是否会改善转移性NSCLC患者的免疫治疗应答。方法PEMBRO-RT和MDACC研究纳入标准:患者年龄≥18岁,患有转移性NSCLC,且有≥1处未经放疗照射的病灶,以便进行射野外应答监测。PEMBRO-RT研究纳入曾接受过化疗患者,MDACC研究纳入曾接受过治疗或新诊断患者。2个研究中的患者均未接受过免疫治疗。在PEMBRO-RT研究中患者被等比例随机分配入组,并根据吸烟状态进行分层(分为<10年组和≥10年组)。MDACC研究的患者根据放疗计划可行性被等比例随机分配入2个受试组。由于联合治疗组的干预本质,每个研究中的放疗均不适用盲法。在2个研究中,不论是否进行放疗,均静脉滴入帕博利珠单抗(每3周200 mg)。在PEMBRO-RT研究中,在放疗(24 Gy 3次分割照射)结束后1周给予第1剂帕博利珠单抗。在MDACC研究中,在第1次放疗(50 Gy 4次分割照射或45 Gy 15次分割照射)同时给予帕博利珠单抗。仅检测未经照射病灶的应答。本研究的终点为最佳射野外(远隔)应答率(ARR)、最佳射野外疾病控制率(ACR)、12周时ARR、12周时ACR、无进展生存期(PFS)和总生存期(OS)。2个研究的意向治疗(ITT)人群均纳入分析。PEMBRO-RT研究(NCT02492568)和MDACC研究(NCT02444741)均在ClinicalTrials.gov上注册。发现纳入148例患者,76例接受帕博利珠单抗治疗,72例接受帕博利珠单抗+放疗治疗。所有患者随访时间中位数为33个月[四分位距(IQR):32.4~33.6]。148例患者中124例(84%)组织学特征为非鳞癌,111例(75%)患者曾经接受过化疗。组间没有基线特征差异,包括PD-L1表达状态和转移灶体积。最常见的照射部位为肺转移灶(39%,28/72)、胸腔内淋巴结(21%,15/72)和非原发灶(17%,12/72)。帕博利珠单抗组和联合治疗组的最佳ARR分别为19.7%(15/76)和41.7%(30/72),OR=2.96,95%CI:1.42~6.20,P=0.0039;最佳ACR分别为43.4%(33/76)和65.3%(47/72),OR=2.51,95%CI:1.28~4.91,P=0.0071;PFS中位数分别为4.4(IQR:2.9~5.9)和9.0个月(IQR:6.8~11.2),HR=0.67,95%CI:0.45~0.99,P=0.045;OS中位数分别为8.7(IQR:6.4~11.0)和19.2个月(IQR:14.6~23.8),OR=0.67,95%CI:0.54~0.84,P=0.0004。在汇总分析中没有发现新的安全问题。解读帕博利珠单抗免疫疗法+放疗显著提高转移性NSCLC患者的应答和改善治疗结局。这些结果需要在三期临床试验中进行验证。 | 陈大卫(翻译) 于金明(校对) Willemijn S M E Theelen Vivek Verma Brian P Hobbs Heike M U Peulen Joachim G J V Aerts Idris Bahce Anna Larissa N Niemeijer Joe Y Chang Patricia M de Groot Quynh-Nhu Nguyen Nathan I Comeaux George R Simon Ferdinandos Skoulidis Steven H Lin Kewen He Roshal Patel John Heymach Paul Baas James W Welsh | 2021 | 中华肿瘤防治杂志2021，28，24： | 49 |
| 2 | The impact of minimally invasive surgeries for the treatment of symptomatic benign prostatic hyperplasia on male sexual function: a systematic review显示文摘使随机化的控制试用和队研究的系统的评论被进行在男性功能上为征兆的良性的 prostatic 增生(BPH ) 的处理为最低限度地侵略的过程的效果评估数据。寻找的研究是与征兆的 BPH 注册了人的试用与激光手术,经尿道的微波治疗( TUMT ),前列腺(金枪鱼)的经尿道的针脱离,前列腺( TEAP )的经尿道的乙醇脱离和高紧张的频率超声( HIFU )被对待,与前列腺( TURP )或假冒的操作的传统的经尿道的切除术比较。72 研究的一个总数被识别,哪个 33 满足了包括标准。33 研究, 21 涉及了激光手术,六与 TUMT,四与金枪鱼并且二与包含信息考虑的 TEAP 男性功能。没有学习关于为男性功能上的 BPH 的 HIFU 的效果是可得到的。我们的分析证明为 BPH 的最低限度地侵略的手术在男可勃起的功能上 TURP 有可比较的效果到那些。一起,分别地,不到 15.4% 病人或 15.2% 将在激光过程, TUMT 和金枪鱼以后可勃起的功能有减少或增加。是与 TURP 观察了,射精的机能障碍(EjD ) 的高发生在有钬, potassium-titanyl-phosphate 和铥激光治疗的 BPH 的治疗以后是普通的(>33.6%) 。TUMT,金枪鱼和 neodymium:yttrium 铝石榴石为 BPH 的视觉激光脱离或空隙的激光凝结有更少的发生 EjD,而是这些过程为 BPH 治疗被认为更少有效什么时候与 TURP 相比。 | Ryan W. Frieben Hao-Cheng Lin Peter E Hinh Francesco Berardinelli Steven E. Canfield Run Wang | 2010 | Asian Journal of Andrology2010，12，4： | 13 |
| 3 | Role of the endothelium in inflammatory bowel diseases显示文摘Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions. | Walter E Cromer J Michael Mathis Daniel N Granger Ganta V Chaitanya J Steven Alexander | 2011 | World Journal of Gastroenterology2011，17，5： | 10 |
| 4 | Comparison between cerebral state index and bispectral index as measures of electroencephalographic effects of sevoflurane using combined sigmoidal Emax model显示文摘目的: 服的州的索引(CSI ) 最近为测量麻醉的深度作为一个 electroencephalographic 监视器被介绍。我们作为 sevoflurane 的措施完成使用二联合 sigmoidal E 最大 模型。 | Dong Woo HAN Olinto-Jose LINARES-PERDOMO Jong Seok LEE Jun Ho KIM Steven E KERN | 2011 | Acta Pharmacologica Sinica2011，32，10： | 9 |
| 5 | Selecting suitable solid organ transplant donors: Reducing the risk of donor-transmitted infections显示文摘Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor-transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompt-ing increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor. | Christopher S Kovacs Jr Christine E Koval David van Duin Amanda Guedes de Morais Blanca E Gonzalez Robin K Avery Steven D Mawhorter Kyle D Brizendine Eric D Cober Cyndee Miranda Rabin K Shrestha Lucileia Teixeira Sherif B Mossad | 2014 | World Journal of Transplantation2014，4，2： | 7 |
| 6 | 勃起功能障碍(ED)的联合疗法显示文摘二十世纪九十年代末二十一世纪初,口服PDE5抑制剂(PDE5Is)的引入在很大程度上革新了性医学领域。目前PDE5I已经成为勃起功能障碍(ED)的首选单一疗法。然而,对一些复杂型ED患者来说,PDE5I单一疗法的疗效还不尽人意。目前越来越多不易治疗的ED病例开始采用联合疗法治疗,但还缺少对当前使用的联合疗法的严格评估。基于此,本综述在Pubmed和Cochrane Library数据库中进行了全面的文献检索.主要检索对象是1990年1月到2010年12月间研究PDE5I单一治疗失败后接受联合疗法的所有相关综述、随机对照试验、队列研究和回顾性研究。同时还对检索所得文献的参考文献进行了人工筛选,获得了其它一些相关的文献资料。目前发表的联合疗法主要包括PDE5I加真空吸引器(VED)、尿道给药、阴茎注射(ICI)、雄激素补充疗法、α-阻断剂,还有其它一些联合疗法。本综述发现,有些联合疗法的初步试验结果是有效的。然而,进行治疗时还是要谨慎,因为近十年来发表的大部分联合疗法相关文章的研究方法有很多问题,比如研究偏见和样本量小等。尽管如此,目前的研究结果还是在为将来复杂型ED的治疗研究方面奠定了坚实的基础。 | Rohit R Dhir Hao-Cheng Lin Steven E Canfield Run Wang | 2011 | Asian Journal of Andrology2011，13，3： | 7 |
| 7 | c-Met signaling in the development of tumorigenesis and chemoresistance: Potential applications in pancreatic cancer显示文摘Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States.The majority of patients are candidates only for palliative chemotherapy,which has proven largely ineffective in halting tumor progression.One proposed mechanism of chemoresistance involves signaling via the mesenchymalepithelial transition factor protein(MET),a previously established pathway critical to cell proliferation and migration.Here,we review the literature to characterize the role of MET in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of MET as a therapeutic target in pancreatic cancer.In this review,we characterize the role of c-Met in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of c-Met as a therapeutic target in pancreatic cancer. | Daniel Delitto Eva Vertes-George Steven J Hughes Kevin E Behrns Jose G Trevino | 2014 | World Journal of Gastroenterology2014，20，26： | 6 |
| 8 | Gelatin degradation assay reveals MMP-9 inhibitors and function of O-glycosylated domain显示文摘AIM: To establish a novel, sensitive and high-throughput gelatinolytic assay to define new inhibitors and compare domain deletion mutants of gelatinase B/matrix metalloproteinase (MMP)-9. METHODS: Fluorogenic Dye-quenched (DQ)TM-gelatin was used as a substrate and biochemical parameters (substrate and enzyme concentrations, DMSO solvent concentrations) were optimized to establish a highthroughput assay system. Various small-sized libraries (ChemDiv, InterBioScreen and ChemBridge) of hetero-cyclic, drug-like substances were tested and compared with prototypic inhibitors. RESULTS: First, we designed a test system with gelatin as a natural substrate. Second, the assay was validated by selecting a novel pyrimidine-2,4,6-trione (barbitu- rate) inhibitor. Third, and in line with present structural data on collagenolysis, it was found that deletion of the O-glycosylated region significantly decreased gelatinolytic activity (kcat/kM ± 40% less than full-length MMP-9). CONCLUSION: The DQTM-gelatin assay is useful in high-throughput drug screening and exosite targeting. We demonstrate that flexibility between the catalytic and hemopexin domain is functionally critical for gelatinolysis. | Jennifer Vandooren Nathalie Geurts Erik Martens Philippe E Van den Steen Steven De Jonghe Piet Herdewijn Ghislain Opdenakker | 2011 | World Journal of Biological Chemistry2011，2，1： | 3 |
| 9 | BCL2 inhibits cell adhesion, spreading, and motility by enhancing actin polymerization显示文摘BCL2 最好作为多功能的 anti-apoptotic 蛋白质被知道。然而,很少在房间粘合剂和活动性事件对它的角色被知道。这里,我们证明 BCL2 可以在房间粘附的规定起一个作用,传播,并且活动性。BCL2 什么时候是在有教养的鼠科、人的房间线,传播的房间,粘附,和活动性的 overexpressed,被损害。与这些结果一致, Bcl2 的损失导致了在 Bcl2 空的老鼠观察的更高的活动性与野类型相比的胚胎的成纤维细胞(MEF ) 房间。房间粘附和活动性的 BCL2 规定的机制可以包含包含 BCL2,肌动朊,和 gelsolin 的建筑群的形成,它看起来机能上地减少 gelsolin 的切断的活动。我们观察到从 overexpressed BCL2 提高了的 MCF-7 和 NIH3T3 房间的 lysate 肌动朊聚合在在 vitro 试金没有房间。BCL2 和 F 肌动朊的共焦的 immunofluorescent 本地化在一致地传播期间证明 BCL2 的那增加的表情导致了增加的 F 肌动朊聚合。因此, BCL2 和 gelsolin 建筑群的形成(它可能包含另外的蛋白质) 看起来在房间粘附和移植的规定起一个关键作用。与癌症转移给房间活动性的确定的关联,这结果可以解释在一些肿瘤房间类型的 BCL2 的表示为什么为转移减少潜力并且与改进耐心的预后被联系。 | Hengning Ke Vandy I Parron Jeff Reece Jennifer Y Zhang Steven K Akiyama John E French | 2010 | Cell Research2010，20，4： | 3 |
| 10 | A confidence limit for the empirical mode decomposition and Hilbert spectral analysis显示文摘 | Huang Norden E Wu Man-Li C Long Steven R Shen Samuel S.P Qu Wendong Gloersen Per Fan Kuang L | 2003 | Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences . 2003 (2037)2003，，2037： | 3 |
| 11 | 血脂、脂蛋白和载脂蛋白作为心肌梗死风险标志物(INTER-HEART研究):在52个国家进行的一项病例对照研究显示文摘背景载脂蛋白作为冠心痛的标志物是否优于血脂和脂蛋白,目前存在广泛争议。本研究旨在对载脂蛋白和胆固醇作为急性心肌梗死风险指标进行比较.
方法在52个国家的12461例急性心肌梗死患者和14637例年龄(±5岁)、性别匹配的对照者中进行了一项有关急性心肌梗死的大型、标准化病例对照研究。获得了9345例急性心肌梗死患者和12120例对照者的非空腹血液样本。测定了血脂、脂蛋白和载脂蛋白浓度,并计算了胆固醇和栽脂蛋白比值通过比较五分位数的上四位与最低位,计算每一总体测值和每一种族组的优势比(0R)及其95%CI以及人群归因危险度(PAR)。
结果载脂蛋白B100(ApoB)/载脂蛋白A1(ApoA1)比值的PAR最高(54%),其每一标准差差别的OR最高(1.59,95%CI1.53~1.64)。LDL胆固醇/HDL-胆固醇比值的PAR为37%;总胆固醇/HDL-胆固醇的PAR为32%,其显著低于ApoB/A1比值的PAR(P〈0.0001)。这些结果在所有种族组、男女两性组及所有年龄组均一致。
结论在所有种族组、男女两性组及所有年龄组,非空腹ApoB/A1比值在评估急性心肌梗死风险方面优于任何胆固醇比值,其应当被引入全世界的临床实践中。 | Matthew J McQueen Steven Hawken Xingyu Wang Stephanie Ounpuu Allan Sniderman Jeffrey Probstfield Krisela Steyn John E Sanderson Mahammad Hasani Emilia Volkova Khawar Kazmi Salim Yusuf 郭战宏(译) | 2008 | 世界临床医学2008，2，6： | 3 |
| 12 | Shoot and root traits in drought tolerant maize(Zea mays L.) hybrids显示文摘This study aimed to investigate the differences in shoot and root traits, and water use and water use efficiency(WUE) in drought tolerant(DT) maize(Zea mays L.) hybrids under full and deficit irrigated conditions. A two-year greenhouse study was conducted with four hybrids(one conventional hybrid, 33D53AM, two commercial DT hybrids, P1151 AM, N75H, and an experimental hybrid, Exp HB) grown under two water regimes(I_(100) and I_(50), referring to 100 and 50% of evapotranspiration requirements). Under water stress, the hybids P1151 AM, N75, and Exp HB showed more drought tolerance and had either greater shoot dry weight or less dry weight reduction than the conventional hybrid(33 D53 AM). However, these three hybrids responded to water stress using different mechanisms. Compared with the conventional hybrid, the two commercial DT hybrids(P1151 AM and N75H) had a smaller leaf area, shoot dry weight, and root system per plant. As a result, these hybrids used less water but had a higher WUE compared with the conventional hybrid. In contrast, the experimental hybrid(ExpHB) produced more shoot biomass by silking stage at both irrigation levels than all other hybrids, but it had relatively lower WUE. The hybrids demonstrated different drought response mechanisms that may require different irrigation management strategies. More investigation and validation are needed under field conditions and in different soil types. | ZHAO Jin XUE Qing-wu Kirk E Jessup HOU Xiao-bo HAO Bao-zhen Thomas H Marek XU Wen-wei Steven R Evett Susan A O'Shaughnessy David K Brauer | 2018 | Journal of Integrative Agriculture2018，17，5： | 3 |
| 13 | Adoptive cell therapy for the treatment of patients with metastatic melanoma显示文摘 | Steven A Rosenberg Mark E Dudley | 2009 | Current Opinion in Immunology2009，，2： | 3 |
| 14 | Immunobiology of hepatocarcinogenesis: Ways to go or almost there?显示文摘Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis.Though treatment modalities are available,mortality from this cancer remains high.Medical therapy with the utilization of biologic compounds such as the Food and Drug Administration approved sorafenib might be the only option that can increase survival.Immunotherapy,with modern pharmacologic developments,is a new frontier in cancer therapy and therefore the immunobiology of hepatocarcinogenesis is under investigation.This review will discuss current concepts of immunobiology in hepatocarcinogenesis along with current treatment modalities employing immunotherapy.The tumor microenvironment along with a variety of immune cells coexists and interplays to lead to tumorigenesis.Tumor infiltrating lymphocytes including CD8+ T cells,CD4+ T cells along with regulatory T cells,tumor associated macrophages,tumor associated neutrophils,myeloid derived suppressor cells,and natural killer cells interact to actively provide anti-tumor or pro-tumor effects.Furthermore,oncogenic pathways such as Raf/mitogenactivated protein kinase/extracellular-signal-regulated kinase pathway,phosphatidyl-3-kinase/AKT/mammalian target or rapamycin,Wnt/β-catenin,nuclear factor-κB and signal transducers and activators of transcription 3 may lead to activation and proliferation of tumor cells and are also considered cornerstones in tumorigenesis.Immunotherapy directed at this complex milieu of cells has been showned to be successful in cancer treatment.The use of vaccines,adoptive cell therapy and immune checkpoint inhibitor modulation are current options for therapy.Further translational research will shed light to concepts such as anti-tumor immunity which can add another alternative in the therapeutic armamentarium. | Pavan Patel Steven E Schutzer Nikolaos Pyrsopoulos | 2016 | World Journal of Gastrointestinal Pathophysiology2016，7，3： | 3 |
| 15 | Quality Improvement Guidelines for the Treatment of Lower Extremity Deep Vein Thrombosis with Use of Endovascular Thrombus Removal显示文摘 | Suresh Vedantham Patricia E. Thorpe John F. Cardella Clement J. Grassi Nilesh H. Patel Hector Ferral Lawrence V. Hofmann Bertrand M. Janne d’Othée Vittorio P. Antonaci Elias N. Brountzos Daniel B. Brown Louis G. Martin Alan H. Matsumoto Steven G. Meranze | 2006 | Journal of Vascular and Interventional Radiology2006，，3： | 3 |
| 16 | Association of types of diabetes and insulin dependency on birth outcomes显示文摘BACKGROUND Diabetes rates among pregnant women in the United States have been increasing and are associated with adverse pregnancy outcomes.AIM To investigate differences in birth outcomes(preterm birth,macrosomia,and neonatal death)by diabetes status.METHODS Cross-sectional design,using linked Missouri birth and death certificates(singleton births only),2010 to 2012(n=204057).Exposure was diabetes non-diabetic,pre-pregnancy diabetes-insulin dependent(PD-I),pre-pregnancy diabetes-non-insulin dependent(PD-NI),gestational diabetes-insulin dependent(GD-I),and gestational diabetes-non-insulin dependent(GD-NI).Outcomes included preterm birth,macrosomia,and infant mortality.Confounders included demographic characteristics,adequacy of prenatal care,body mass index,smoking,hypertension,and previous preterm birth.Bivariate and multivariate logistic regression assessed differences in outcomes by diabetes status.RESULTS Women with PD-I,PD-NI,and GD-I remained at a significantly increased odds for preterm birth(aOR 2.87,aOR 1.77,and aOR 1.73,respectively)and having a very large baby[macrosomia](aOR 3.01,aOR 2.12,and aOR 1.96,respectively);in reference to non-diabetic women.Women with GDNI were at a significantly increased risk for macrosomia(aOR1.53),decreased risk for their baby to die before their first birthday(aOR 0.41)and no difference in risk for preterm birth in reference to non-diabetic women.CONCLUSION Diabetes is associated with the poor birth outcomes.Clinical management of diabetes during pregnancy and healthy lifestyle behaviors before pregnancy can reduce the risk for diabetes and poor birth outcomes. | Pamela K Xaverius Steven W Howard Deborah Kiel Jerry E Thurman Ethan Wankum Catherine Carter Clairy Fang Romi Carriere | 2022 | World Journal of Clinical Cases2022，10，7： | 2 |
| 17 | Inflammation and Alzheimer’s disease显示文摘 | Haruhiko Akiyama Steven Barger Scott Barnum Bonnie Bradt Joachim Bauer Greg M Cole Neil R Cooper Piet Eikelenboom Mark Emmerling Berndt L Fiebich Caleb E Finch Sally Frautschy W.S.T Griffin Harald Hampel Michael Hull Gary Landreth Lih–Fen Lue Robert Mrak | 2000 | Neurobiology of Aging2000，，3： | 2 |
| 18 | Community-level physiological profiles of bacteria and fungi: plate type and incubation temperature influences on contrasting soils显示文摘 | Aimée T Classen Sarah I Boyle Kristin E Haskins Steven T Overby Stephen C Hart | | FEMS Microbiology Ecology0，，： | 2 |
| 19 | Reoperation for prosthetic aortic valve obstruction in the era of echocardiography: trends in diagnostic testing and comparison with surgical findings显示文摘 | Steven E Girard Fletcher A Miller Thomas A Orszulak Charles J Mullany Samantha Montgomery William D Edwards Henry D Tazelaar Joseph F Malouf A.Jamil Tajik | 2001 | Journal of the American College of Cardiology2001，，2： | 2 |
| 20 | 基于FANS的温室风机通风性能测试显示文摘试验采用Fansassessmentnumerationsystem(FANs)为现场监测系统,利用位置上下移动持续运行的螺旋桨风速计和静压传感器对风机通风性能进行测试。试验共测定3个玻璃温室内3种类型共9个排风风机在不同工况下静压5.O~61.5Pa范围内的通风量和能源消耗。结果显示,风机防护网的存在及清洁状况对通风量的影响低于5%;塑料百叶窗风机比相同配置的铝制百叶窗风机通风量和能效分别平均高13.1%、15.1%;参数完全相同的风机能效差异最高达12.7%;胶带驱动的风机转速减少16.1%时通风量平均降低38.7%;温室内静压超过30Pa时风机能耗显著增加。 | 张智 Steven E Ford Richard S Gates 邹志荣 | 2014 | 农业机械学报2014，45，11： | 2 |
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