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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 | Contribution of oxidative stress to pulmonary arterial hypertension显示文摘Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI 2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure. | Vincent G DeMarco Adam T Whaley-Connell James R Sowers Javad Habibi Kevin C Dellsperger | 2010 | World Journal of Cardiology2010，2，10： | 21 |
| 3 | Calcium signaling and T-type calcium channels in cancer cell cycling显示文摘Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel isminimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2+ channel blockers may be useful in the treatment of certain types of cancers. | James T Taylor Xiang-Bin Zeng Jonathan E Pottle Kevin Lee Alun R Wang Stephenie G Yi lennifer A S Scruggs Suresh S Sikka Ming Li | 2008 | World Journal of Gastroenterology2008，14，32： | 12 |
| 4 | 在结肠和直肠的癌症的淋巴节点收获: 当前的考虑显示文摘 The prognostic significance of identifying lymph node(LN) metastases following surgical resection for colon and rectal cancer is well recognized and is reflected in accurate staging of the disease.An established body of evidence exists,demonstrating an association between a higher total LN count and improved survival,particularly for node negative colon cancer.In node positive disease,however,the lymph node ratios may represent a better prognostic indicator,although the impact of this on clinical treatment has yet to be universally established.By extension,strategies to increase surgical node harvest and/or laboratory methods to increase LN yield seem logical and might improve cancer staging.However,debate prevails as to whether or not these extrapolations are clinically relevant,particularly when very high LN counts are sought.Current guidelines recommend a minimum of 12 nodes harvested as the standard of care,yet the evidence for such is questionable as it is unclear whether an increasing the LN count results in improved survival.Findings from modern treatments,including down-staging in rectal cancer using pre-operative chemoradiotherapy,paradoxically suggest that lower LN count,or indeed complete absence of LNs,are associated with improved survival;implying that using a specific number of LNs harvested as a measure of surgical quality is not always appropriate.The pursuit of a sufficient LN harvest represents good clinical practice;however,recent evidence shows that the exhaustive searching for very high LN yields may be unnecessary and has little in? uence on modern approaches to treatment. | James R McDonald Andrew G Renehan Sarah T O’Dwyer Najib Y Haboubi | 2012 | World Journal of Gastrointestinal Surgery2012，4，1： | 8 |
| 5 | Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression显示文摘 | Victoria G Weis Josane F Sousa Bonnie J LaFleur Ki Taek Nam Jared A Weis Paul E Finke Nadia A Ameen James G Fox James R Goldenring | 2013 | Gut2013，，9： | 3 |
| 6 | The mechanical properties of 316L/304L stainless steels, Alloy 718 and Mod 9Cr-lMo after irradiation in a spallation environment显示文摘 | Maloy S A James M R Willcutt G | 2001 | Journal of Nuclear material2001，296，13： | 1 |
| 7 | COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease显示文摘 | Wayne A Ray C Michael Stein James R Daugherty Kathi Hall Patrick G Arbogast Marie R Griffin | 2002 | The Lancet2002，，9339： | 1 |
| 8 | Separation of trace metal complexes for analysis of samples of high salt content by inductively coupled plasma mass spectrometry显示文摘 | Michael R Plantz James S Fritz Fred G | 1989 | Anal Chem1989，61，2： | 1 |
| 9 | The influence of pH and media composition on the uptake of inorganic selenium by Chlamydomonas reinhardtii显示文摘 | Gerhardt F R James G S | 1996 | Environmental Toxicology and Chemistry1996，15，9： | 1 |
| 10 | Determination of strains in soils by X-ray method显示文摘 | ROSCOE K H ARTHUR J R F JAMES R G | 1963 | Civil Engineering (London)1963，58，685： | 1 |
| 11 | Estimating Within-group Interrater Reliability with and Without Response Bias显示文摘 | JAMES L R DEMAREE R G WOLF G | 1984 | Journal of Applied Psychology1984，69，1： | 1 |
| 12 | Cerebral blood flow and neuropsychological asymmetries in unilateral stroke显示文摘 | GREGORY G BROWN JAMES R | 1991 | Stroke1991，22，： | 1 |
| 13 | Genome, transcriptome, and secretome analysis of wood decay fungus Postia placenta supports unique mechanisms of lignocellulose conversion 显示文摘 | Martinez D Challacombe J Morgenstern 1 Hibbett D Schmoll M Kubicek CP Ferreira P Ruiz-Duenas FJ Martinez AT Kersten P Hammel KE Wymelenberg AV Gaskell J Lindquist E Sabat G BonDurant SS Larrondo LF Canessa P Vicuna R Yadav J Doddapaneni H Subramanian V Pisabarro AG Lavin JL Oguiza JA Master E Henrissat B Coutinho PM Harris P Magnuson JK Baker SE Bruno K Kenealy W Hoegger PJ Kties U Ramaiya P kucas S Salamov A Shapiro H Tu H Chee CL Misra M Xie G Teter S Yaver D James T Mokrejs M Pospisek M Grigoriev IV Brettin T Rokhsar D Berka R Cullen D | 2009 | PNAS2009，106，6： | 1 |
| 14 | Determination of stress fields during plane strain of sand mass显示文摘 | ARTHUR J R F JAMES R G ROSCOE K H | 1964 | Geotechnique1964，14，4： | 1 |
| 15 | The role of AI in CSH:NMR,XRD, and compositional results for precipi- tated samples显示文摘 | SUN G K FRANCIS Y J JAMES KIRKPATRICK R | 2006 | Cement and Concrete Research2006，36，1： | 1 |
| 16 | RWG: An Assessment of Within-group Interrater Agreement显示文摘 | JAMES L R DEMAREE R G WOLF G | 1993 | Journal of Applied Psychology1993，78，2： | 1 |
| 17 | Effect of down- regulation of ethylene biosynthesis on fruit flavor complex in apple fruit显示文摘 | DANDEKAR A M TEO G DEFILIPPI B G URATSU S L PASSEY A J KADER A A STOW J R COLGAN R J JAMES D J | 2004 | Transgenic Research2004，13，： | 1 |
| 18 | Estimating within group interrater reliability with and without response bias显示文摘 | JAMES L R DEMAREE R G WOLF | 1985 | J Appl Psyehol1985，69，1： | 1 |
| 19 | Estimating Within-group Interrater Reliability With and Without Response Bias 显示文摘 | James L R Demaree R G Wolf G | 1984 | Journal of Applied Psychology1984，，69： | 1 |
| 20 | Electrophilic bond insertion by cationic nitrogen显示文摘 | Peter T Lansbury James G Colson Norman R Mancuso | 1964 | American Chemical Society1964，86，： | 1 |
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