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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 | Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort显示文摘BACKGROUND Colorectal cancer(CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2(COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans.AIM To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile.METHODS Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge(Barcelona, Spain) and Germans Trias i Pujol University Hospital(Campus Can Ruti)(Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F(PNGase F). Prostaglandin E2(PGE2) levels were determined using a specific ELISA. 1 H high resolution magic angle spinning(HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer(nano LC-MS/MS) using a QExactive HF orbitrap MS.RESULTS Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover,HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity,DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing.CONCLUSION In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile. | Patricia Prieto Rafael I Jaén Daniel Calle María Gómez-Serrano Estefanía Nú?ez María Fernández-Velasco Paloma Martín-Sanz Sergio Alonso Jesús Vázquez Sebastián Cerdán Miguel ángel Peinado Lisardo Boscá | 2019 | World Journal of Gastroenterology2019，25，4： | 4 |
| 3 | Immunogenetic factors driving formation of ultralong VH CDR3 in Bos taurus antibodies显示文摘The antibody repertoire of Bos taurus is characterized by a subset of variable heavy(VH)chain regions with ultralong third complementarity determining regions(CDR3)which,compared to other species,can provide a potent response to challenging antigens like HIV env.These unusual CDR3 can range to over seventy highly diverse amino acids in length and form uniqueβ-ribbon‘stalk’and disulfide bonded‘knob’structures,far from the typical antigen binding site.The genetic components and processes for forming these unusual cattle antibody VH CDR3 are not well understood.Here we analyze sequences of Bos taurus antibody VH domains and find that the subset with ultralong CDR3 exclusively uses a single variable gene,IGHV1-7(VHBUL)rearranged to the longest diversity gene,IGHD8-2.An eight nucleotide duplication at the 3′end of IGHV1-7 encodes a longer V-region producing an extended Fβ-strand that contributes to the stalk in a rearranged CDR3.A low amino acid variability was observed in CDR1 and CDR2,suggesting that antigen binding for this subset most likely only depends on the CDR3.Importantly a novel,potentially AID mediated,deletional diversification mechanism of the B.taurus VH ultralong CDR3 knob was discovered,in which interior codons of the IGHD8-2 region are removed while maintaining integral structural components of the knob and descending strand of the stalk in place.These deletions serve to further diversify cysteine positions,and thus disulfide bonded loops.Hence,both germline and somatic genetic factors and processes appear to be involved in diversification of this structurally unusual cattle VH ultralong CDR3 repertoire. | Thaddeus C Deiss Melissa Vadnais Feng Wang Patricia L Chen Ali Torkamani Waithaka Mwangi Marie-Paule Lefranc Michael F Criscitiello Vaughn V Smider | 2019 | Cellular & Molecular Immunology2019，16，1： | 4 |
| 4 | Mortality Associated With Atrial Fibrillation in Patients With Myocardial Infarction: A Systematic Review and Meta-Analysis显示文摘 | Patricia Jabre Véronique L. Roger Mohammad H. Murad Alanna M. Chamberlain Larry Prokop Frédéric Adnet Xavier Jouven | 2011 | Circulation2011，，15： | 2 |
| 5 | Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2R[gamma]c-deficient mice显示文摘 | Sarry Jean-Emmanuel Murphy Kathleen Perry Robin Sanchez Patricia V Secreto Anthony Keefer Cathy Swider Cezary R Strzelecki Anne-Claire Cavelier Cindy Récher Christian Mansat-De Mas Véronique Delabesse Eric Danet-Desnoyers G Carroll Martin | 2011 | Journal of Clinical Investigation2011，，1： | 2 |
| 6 | Enhancing the Trust-based Recommendation Process with Explicit Dis-trust显示文摘 | Patricia V Nele V Chris C | 2013 | ACM Transactions on the Web2013，7，2： | 1 |
| 7 | Nuclear co-expression of p14 ^{ARF} and p16 ^{INK4A} in uterine cervical cancer-derived cell lines containing HPV显示文摘 | Salvador Vázquez-Vega Lilia Patricia Sánchez-Suárez Adriana Contreras-Paredes Emilio Castellanos-Juárez Rubicelia Pe?arroja-Flores Marcela Lizano-Soberón Rafael Andrade-Cruz Alejandro García-Carrancá Luis Benítez-Bribiesca | 2010 | Cancer Biomarkers2010，，6： | 1 |
| 8 | The effect of ionic products from bioactive glass dissolution on osteoblast proliferation and collagen production显示文摘 | Patricia V Marivalda M P Alfredo M G | 2004 | Biomaterials2004，25，： | 1 |
| 9 | Tumor angiogensis and tissue factor expression during hepatocellular carcinoma progression in a transgenic mouse mode显示文摘 | Evelyhe D Patricia H Ande V | 2003 | J Hepatol2003，38，6： | 1 |
| 10 | Preparation, characterization and use of V 2 O 5 -TiO 2 mixed xerogels as catalysts for sustainable oxidation with hydrogen peroxide of 2,3,6-trimethylphenol显示文摘 | Magdalena Palacio Paula I. Villabrille Gustavo P. Romanelli Patricia G. Vázquez Carmen V. Cáceres | 2012 | Applied Catalysis A General2012，，： | 1 |
| 11 | Virtualhysterosalpingography: Experiencewith over 1000 consecutive patients显示文摘 | Patricia C Carlos C Javier V | 2011 | Abdom Imaging2011，36，： | 1 |
| 12 | Litigation Risk, lntemlediation, and the Underprieing of Initial Public Offierings 显示文摘 | HUGHES PATRICIA J AN JAN V THAKOR | 1992 | Review of Financial Studies1992，5，： | 1 |
| 13 | Effect of copper on the photochemical efficiency,growth,and chlorophyll a biomass of natural phytoplankton assemblages Environmental显示文摘 | PATRICIA P R PATRICIA E V RICARDO B | 2006 | Toxicology and Chemistry2006，25，1： | 1 |
| 14 | 查看详情显示文摘 | María L G P Patricia P B Roberto R G José L M V Antonia G F | | 0，，27： | 1 |
| 15 | Tumor angiogenesis and tissue factor expression during hepatocellular carcinoma progression in a transgenic mouse model显示文摘 | EVELYHE D PATRICIA H ANDE V | 2003 | J Hepatol2003，38，6： | 1 |
| 16 | Role of Leptin in the Activation of Immune Cells显示文摘 | Patricia Fernández-Riejos Souad Najib Jose Santos-Alvarez Consuelo Martín-Romero Antonio Pérez-Pérez Carmen González-Yanes Víctor Sánchez-Margalet Giuseppe Matarese | 2010 | Mediators of Inflammation2010，，： | 1 |
| 17 | Opportunities and Challenges in Using Epidemiologic Methods to Monitor Drug Safety in the Era of Large Automated Health Databases显示文摘 | Elizabeth B Andrews Andrea V Margulis Patricia Tennis | 2014 | Curr Epidemiol Rep2014，1，： | 1 |
| 18 | Transport of protein across lymphatic endothelium in the rat kidney 显示文摘 | Yang V V Patricia J O'Morchoe C C | 1981 | Microvasc Res1981，21，2： | 1 |
| 19 | A novel,rapid assay for detection and differentiation of serotype-c antibodies to Venezuelane quine encephalitis complex alphaviruses显示文摘 | Eryu W Slobodan P Patricia V | | 0，，06： | 1 |
| 20 | Functional properties of coffee and coffee by-products显示文摘 | Patricia Esquivel V i ctor M Jim 6 nez | 2012 | Food Research International2012，46，2： | 1 |
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