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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 | Helicobacter pylori in dental plaque and stomach of patients from Northern Brazil显示文摘AIM: To establish whether virulence factor genes vacA and cagA are present in Helicobacter pylori (H. pylori) retrieved from gastric mucosa and dental plaque in pa-tients with dyspepsia. METHODS: Cumulative dental plaque specimens and gastric biopsies were submitted to histological exami-nation, rapid urease test and polymerase chain reac-tion (PCR) assays to detect the presence of cagA and vacA polymorphisms.RESULTS: Detection of H. pylori from dental plaque and gastric biopsy samples was greater by PCR com-pared to histological examination and the rapid ure-ase test. DNA from H. pylori was detected in 96% of gastric mucosa samples and in 72% of dental plaque samples. Sixty-three (89%) of 71 dental plaque sam-ples that were H. pylori-positive also exhibited identical vacA and cagA genotypes in gastric mucosa. The most common genotype was vacAs1bm1 and cagA positive, either in dental plaque or gastric mucosa. These viru-lent H. pylori isolates were involved in the severity of clinical outcome.CONCLUSION: These pathogenic strains were found simultaneously in dental plaque and gastric mucosa, which suggests that gastric infection is correlated with the presence of H. pylori in the mouth. | Mnica Baraúna Assumpo Luisa Caricio Martins Hivana Patricia Melo Barbosa Katarine Antonia dos Santos Barile Sintia Silva de Almeida Paulo Pimentel Assumpo Tereza Cristina de Oliveira Corvelo | 2010 | World Journal of Gastroenterology2010，16，24： | 29 |
| 3 | WJD 5^(th) Anniversary Special Issues(2): Type 2 diabetes Inflammation in diabetic kidney disease显示文摘Diabetes mellitus entails significant health problems worldwide.The pathogenesis of diabetes is multifactorial,resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events,with metabolic and hemodynamic alterations.In this context,inflammation has emerged as a key pathophysiology mechanism.New pathogenic pathways will provide targets for prevention or future treatments.This review will focus on the implications of inflammation in diabetes mellitus,with special attention to inflammatory cytokines. | Patricia M García-García María A Getino-Melian Virginia Domínguez-Pimentel Juan F Navarro-Gonzalez | 2014 | World Journal of Diabetes2014，5，4： | 26 |
| 4 | Role of ion channels in gastrointestinal cancer显示文摘In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell.The functions of ion channels in the gastrointestinal(GI)tract influence a variety of cellular processes,many of which overlap with these hallmarks of cancer.In this review we focus on the roles of the calcium(Ca^2+),sodium(Na^+),potassium(K^+),chloride(Cl^-)and zinc(Zn^2+)transporters in GI cancer,with a special emphasis on the roles of the KCNQ1 K+channel and CFTR Cl-channel in colorectal cancer(CRC).Ca^2+is a ubiquitous second messenger,serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle,apoptosis,and migration.Various members of the TRP superfamily,including TRPM8,TRPM7,TRPM6 and TRPM2,have been implicated in GI cancers,especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer.Voltage-gated sodium channels(VGSCs)are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells.The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples.Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression.Zn2+transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers,in particular,ZIP4 up-regulation in pancreatic cancer(PC).More than 70 K+channel genes,clustered in four families,are found expressed in the GI tract,where they regulate a range of cellular processes,including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract.Several distinct types of K+channels are found dysregulated in the GI tract.Notable are hERG1 upregulation in PC,gastric cancer(GC)and CRC,leading to enhanced cancer angiogenesis and invasion,and KCNQ1 down-regulation in CRC,where KCNQ1 expression is associated with enhanced disease-free survival in stage II,III,and IV disease.Cl-channels are critical for a range of cellular and tissue processes in the GI tract,especially fluid balance in the colon.Most notable is CFTR,whose deficiency leads to mucus blockage,microbial dysbiosis and inflammation in the intestinal tract.CFTR is a tumor suppressor in several GI cancers.Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC.Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels(CLIC1,3&4)and the chloride channel accessory proteins(CLCA1,2,4).CLIC1&4 are upregulated in PC,GC,gallbladder cancer,and CRC,while the CLCA proteins have been reported to be down-regulated in CRC.In summary,it is clear,from the diverse influences of ion channels,that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression.Further,because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation,they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs. | Kyle J Anderson Robert T Cormier Patricia M Scott | 2019 | World Journal of Gastroenterology2019，25，38： | 19 |
| 5 | Persistent occult hepatitis B virus infection:Experimental findings and clinical implications显示文摘Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences. | Patricia M Mulrooney-Cousins Tomasz I Michalak | 2007 | World Journal of Gastroenterology2007，13，43： | 17 |
| 6 | Interleukin-1 and TNF-α polymorphisms and Helicobacter pylori in a Brazilian Amazon population显示文摘AIM:To study the association between Interleukin-1(IL-1)and tumor necrosis factor(TNF)-αpolymorphisms,infection by Helicobacter pylori(H pylori)and the development of gastrointestinal diseases.METHODS:Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers.The polymorphisms in IL-1βand TNF-αgenes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method(PCRRFLP)and those from IL-1RN with PCR.The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology.The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS:A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL1RN*2 was more frequent among patients with gastric ulcers and adenocarcinoma.Carriers of the allele ILRN*2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma,as well as a higher degree of inflammation and neutrophilic activity in the gastric mucosa.CONCLUSION:Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma. | Hivana Patricia Melo Barbosa Luisa Caricio Martins Sidney Emanuel Batista dos Santos Samia Demachki Mnica Baraúna Assumpo Charliana Damasceno Arago Tereza Cristina de Oliveira Corvelo | 2009 | World Journal of Gastroenterology2009，15，12： | 17 |
| 7 | 燃煤飞灰吸附脱汞能力的实验研究显示文摘运用煤岩学分类相关理论对燃煤飞灰岩相组成进行了系统定量分析,并采用固定床汞吸附反应系统对不同电厂飞灰吸附汞的能力进行了详细研究,结果表明:不同的飞灰对汞均有一定的吸附能力,其中以烟煤飞灰CTSR和CTL的富碳组分对汞的吸附能力最强,其吸附能力分别为10.3和9.36μg/g,与商业活性炭捕获能力相当;飞灰中汞的含量与其含炭量和比表面积并无明显的相关性.揭示了飞灰颗粒岩相组成,分析了飞灰脱汞能力的影响因素.不同飞灰碳颗粒类型脱汞性能差异明显,各向异性碳颗粒尤其是多孔网状结构碳含量是决定飞灰脱汞能力的主要因素. | 赵永椿 张军营 刘晶 DíAZ-SOMOANO Mercedes ABAD-VALLE Patricia MARTíNEZ-TARAZONA M Rosa 郑楚光 | 2010 | 中国科学:技术科学2010，40，4： | 15 |
| 8 | Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning显示文摘AIM:To assess the relationship between preoperative computed tomography(CT)and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data.METHODS:A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy.Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens.Inter-and intra-observer variations in CT measurements were assessed.Survival data were collected.RESULTS:There was a weak correlation between CT and pathological tumor length(r=0.30,P=0.025).CT lengths were longer than pathological lengths in 68%(38/56)of patients with a mean difference of 1.67 cm(95%CI:1.18-2.97).The mean difference in measurements by two radiologists was 0.39 cm(95% CI:-0.59-1.44).The mean difference between repeat CT measured tumor length(intra-observer variation) were 0.04 cm(95%CI:-0.59-0.66)and 0.47 cm (95%CI:-0.53-1.47).When stratified,patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length(r =0.69,P=0.0014,n=37)than patients that did(r= 0.13,P=0.43,n=19).Median survival with CT tumor length>5.6 cm was poorer than with smaller tumors,but the difference was not statistically significant.CONCLUSION:Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions,particularly for planning radiotherapy. | Karim Sillah Luke R Williams Hans-Ulrich Laasch Azeem Saleem Gillian Watkins Susan A Pritchard Patricia M Price Catharine M West Ian M Welch | 2010 | World Journal of Gastrointestinal Oncology2010，2，4： | 10 |
| 9 | Orally administered extract from Prunella vulgaris attenuates spontaneous colitis in mdr1a^(-/-) mice显示文摘AIM: To investigate the ability of a Prunella vulgaris(P. vulgaris) ethanolic extract to attenuate spontaneous typhlocolitis in mdr1a-/- mice. METHODS: Vehicle(5% ethanol) or P. vulgaris ethanolic extract(2.4 mg/d) were administered daily by oral gavage to mdr1a-/- or wild type FVBWT mice from 6 wk of age up to 20 wk of age. Clinical signs of disease were noted by monitoring weight loss. Mice experiencingweight loss in excess of 15% were removed from the study. At the time mice were removed from the study, blood and colon tissue were collected for analyses that included histological evaluation of lesions, inflammatory cytokine levels, and myeloperoxidase activity. RESULTS: Administration of P. vulgaris extracts to mdr1a-/- mice delayed onset of colitis and reduced severity of mucosal inflammation when compared to vehicle-treated mdr1a-/- mice. Oral administration of the P. vulgaris extract resulted in reduced(P < 0.05) serum levels of IL-10(4.6 ± 2 vs 19.4 ± 4), CXCL9(1319.0 ± 277 vs 3901.0 ± 858), and TNFα(9.9 ± 3 vs 14.8 ± 1) as well as reduced gene expression by more than two-fold for Ccl2, Ccl20, Cxcl1, Cxcl9, IL-1 α, Mmp10, VCAM-1, ICAM, IL-2, and TNFα in the colonic mucosa of mdr1a-/- mice compared to vehicle-treated mdr1a-/-mice. Histologically, several microscopic parameters were reduced(P < 0.05) in P. vulgaris-treated mdr1a-/-mice, as was myeloperoxidase activity in the colon(2.49 ± 0.16 vs 3.36 ± 0.06, P < 0.05). The numbers of CD4+ T cells(2031.9 ± 412.1 vs 5054.5 ± 809.5) and germinal center B cells(2749.6 ± 473.7 vs 4934.0 ± 645.9) observed in the cecal tonsils of P. vulgaris-treated mdr1a-/- were significantly reduced(P < 0.05) from vehicle-treated mdr1a-/- mice. Vehicle-treated mdr1a-/- mice were found to produce serum antibodies to antigens derived from members of the intestinal microbiota, indicative of severe colitis and a loss of adaptive tolerance to the members of the microbiota. These serum antibodies were greatly reduced or absent in P. vulgaris-treated mdr1a-/- mice. CONCLUSION: The anti-inflammatory activity of P. vulgaris ethanolic extract effectively attenuated the severity of intestinal inflammation in mdr1a-/- mice. | Kelley MK Haarberg Meghan J Wymore Brand Anne-Marie C Overstreet Catherine C Hauck Patricia A Murphy Jesse M Hostetter Amanda E Ramer-Tait Michael J Wannemuehler | 2015 | World Journal of Gastrointestinal Pharmacology and Therapeutics2015，6，4： | 8 |
| 10 | 大气二氧化氮与每日总死亡率、心血管和呼吸系统疾病死亡率的短期关联:398个城市的多中心分析显示文摘目的:采用统一的分析方案,评估全球多个国家/地区的二氧化氮(NO_(2))与总死亡率、心血管和呼吸系统疾病死亡率之间的短期关联。研究设计:采用两阶段的时间序列分析方法、过度离散的广义线性模型和多水平meta分析。研究地点:22个低到高收入国家/地区的398个城市。主要结局指标:1973—2018年逐日总死亡人数(6280万人)、心血管疾病死亡人数(1970万人)和呼吸系统疾病死亡人数(550万人)。结果:平均而言,NO_(2)浓度在滞后1天(前1天)每增加10μg/m^(3),会导致总死亡率、心血管和呼吸系统疾病死亡率分别增加0.46%(95%可信区间0.36%~0.57%)、0.37%(0.22%~0.51%)、0.47%(0.21%~0.72%)。在对共污染物(PM_(10)、PM_(2.5)、臭氧、二氧化硫和一氧化碳)进行调整后,这些关联仍然很稳定。所有3种死因的暴露-反应曲线几乎是线性的,没有明显的阈值。在398个城市中,可归因于高过假定零水平的NO_(2)浓度造成的死亡比例为1.23%(95%可信区间0.96%~1.51%)。结论:这项多中心研究提供了关于NO_(2)短期暴露与总死亡率、心血管和呼吸系统死亡风险之间的独立和线性关联的关键证据,说明通过加强NO_(2)的控制和监管限制标准,可获得人群水平的健康收益。 | 孟夏 刘聪(校) 陈仁杰 郑湃(译) 阚海东(校) Francesco Sera Ana Vicedo-Cabrera Ai Milojevic Maria Guo Yuming Tong Shilu Micheline de Sousa Zanotti Stagliorio Coelh Paulo Hilario Nascimento Saldiva Eric Lavigne Patricia Matus Correa Nicolas Valdes Ortega Samuel Osorio Garcia Jan Kysely Ales Urban Hans Orru Marek Maasikmets Jouni J K Jaakkola Niilo Ryti Veronika Huber Alexandra Schneider Klea Katsouyanni Antonis Analitis Masahiro Hashizume Yasushi Honda Chris Fook Sheng Ng Baltazar Nunes João Paulo Teixeira Iulian Horia Holobaca Simona Fratianni Ho Kim Aurelio Tobias Carmeníniguez Bertil Forsberg ChristoferÅström Martina S Ragettli Yue-Liang Leon Guo Shih-Chun Pan Shanshan Li Michelle L Bell Antonella Zanobetti Joel Schwartz Tangchun Wu Antonio Gasparrini | 2021 | 英国医学杂志中文版2021，24，8： | 7 |
| 11 | 癌症的时间生物学:治疗癌症的时间重要吗?(英文)显示文摘我们周围的世界是一个已知有生命进化的世界,一个在不停变化的世界.这些变化多数是周期性的.这些周期性动态变化起源于地球、太阳和月亮之间有规律的时空关系,这种关系正是节律产生的本质.日夜的交替、日照时间的季节性变化以及由于过强或过弱的寻常节律导致的突发性气候变化,所有这些使得地球生命节律得以产生(火星生命尚未深入研究).这些近乎完美的节律变化引起了每日两次(昼夜)和每月一次(月经)的生命节律及相呼应的复杂生理变化.这些信息均已被深深地编入在我们的基因密码中.还有更低频率的节律,如:反映太阳黑子活动的规律(周期为10.5年)及世纪性周期或更长周期的节律,如气候的变更.所有这些节律都具有生物学意义.过去30年中,这些节律对健康、对疾病和宿主间平衡的影响已日显明朗.这些概念早在三世纪前的西方医学中就已经发现,在几千年前的中国传统医学中就有描述和应用.中医的因时施治和时令用药等正合此理.该文通过深入的理论探讨和详实的实验数据阐述了在认识、预防、诊断和治疗癌症时要仔细地考虑时间的科学基础,也为这方面的中医理论提供了现代科学的依据.时间生物学(chronobiology)是一门研究生物现象节律性变化的科学.这种动态生物学研究揭示的是在生物物理和生物化学过程中,以时间为基础的变化规律.最常见的生物节律按其周期的长短有3种:以(24±4)h为周期的昼夜节律,以(30±7)d为周期的月节律,和以(12±2)月为周期的年节律.目前,对昼夜生物节律现象研究的最多,对其生物学意义了解也最深.生物节律最基本的特性有:①内源性和遗传性;②外界刺激可调节生物节律;③在没有外界时间相关信息提示时仍可保持节律性.机体内的生物钟是维持这些节律的基本结构,下丘脑的视交叉上核是这个时间中枢的所在.外界环境,如光线或日照每天都对这个时间中枢进行调整,并进而影响机体的许多生理功能,如睡眠、体温、激素分泌及细胞增殖周期等,使得健康机体中这些生理过程都维持着显著的昼夜周期性节律.不适当外界环境刺激,尤其是长期在夜间暴露于强光之下(如从事护士和娱乐业的人员),可导致机体生物钟的持续紊乱.这种持续的紊乱可导致睡眠紊乱、激素分泌失衡、精神状态失调及冠心病等.近来流行病学调查还发现这种紊乱和乳腺癌、结肠癌的发病有关.生物体内存在维持时间节律的分子机制,这就是生物钟基因.它存在于生物钟中枢及每一个外周组织中.机体的时间节律正是由这些生物钟基因及受其调控的相关基因(钟控基因,约占人基因的10%~15%)的协同表达所致.目前已知正常增生活跃的组织中,DNA合成和细胞分裂都具有明显的昼夜周期性节律.其中以对骨髓、肠道粘膜研究得最多,因为这两个组织对许多细胞毒化疗药物都很敏感,造成它们损伤的程度是许多化疗药物及放疗应用受限的原因.癌组织也有昼夜时间节律,这表现在:①它在宿主体内的生长有时间节律;②癌细胞的增生和凋亡受生物钟基因调控;③同一种抗癌药物,在某些时间给药可能是有效的,而在另外一些时间给药则不仅无效反而造成对正常组织损伤.临床的随机抽样调查表明只要用药时间适当,细胞毒化疗药物的毒性可以减弱,药物的剂量可以加大,治疗效果可以改善,癌症病人的生存可以延长.对人体癌细胞在一天中某一时刻、处于某一细胞周期阶段的细胞比例的研究,目前仍需要系列地采集一天内不同时段的组织标本来完成.我们曾对一例恶性表皮癌及周边正常皮肤进行了系列的、跨24小时的研究.结果表明病人在日常光照环境中,其癌症及正常表皮细胞的分裂都是有规律的、时多时少的过程.这种动态的昼夜变化节律毫无疑问在癌症的化疗和放疗中有很大应用价值. 动物和临床实验已证明调整用药时间的重要性和可行性.有一个典型的动物实验可证明药物毒性和用药时间的关系.如果连续6 d在白天或其睡眠期给小鼠注射一定剂量的阿拉伯糖苷(arcC),只有15%的小鼠会因药物毒性而死亡;而如果在晚上或其活动期注射同样剂量的药物,则小鼠的死亡率会增加至75%.用表阿霉素(doxorubicin)和顺铂(cisplatin)治疗晚期卵巢癌的临床研究是另一个例子.对病人采用晚间注射表阿霉素和早晨注射顺铂的治疗方案产生副作用的机率明显高于采用早晨注射表阿霉素和晚间注射顺铂的方案.5氟尿嘧啶(5-Fu)的抗癌疗效和副作用的产生也有很强的时间依赖性.对这种时间依赖性的机制现已有所了解.二氢嘧啶脱氢酶(DPD)是氟嘧啶代谢的限速酶,它可以将5-Fu及代谢衍生物转化成无细胞毒性的产物而排出体外.研究表明DPD在大鼠肝脏中的表达是有昼夜节律的,正是DPD在肝脏有节律地代谢、清除5-Fu及代谢衍生物才使得5-Fu的疗效和副作用有很强的时间依赖性.抗癌药物的发展是一个复杂、代价高昂和充满冒险的过程.许多化合物或衍生物被设计、合成或生产,这些备选药物可能针对细胞周期的不同阶段或机制,其中很多备选药物在层层筛选中因为毒性、特异性或有效性等问题而被弃用.如果一个备选药物被证明有效或完全无效,则取舍的结果将是完全不同的,此时请别忘记考虑用药时间的因素.我们的研究表明人体和癌症之间的平衡存在着日、月或季节的节律性变化.了解和承认这些日、月或季节性变化可帮助我们更好地预防、诊断,更安全、有效地治疗人类的癌症.在我们这个以24/7(24小时/日,7日/周)为时间周期单位的世界里,一个现代化、工业化的世界,不适当的环境污染,包括光的污染(如夜间强光照射)日渐增多.它所造成的人的生物钟节律的紊乱是显著的.遗憾的是只有少数医学科学家重视和正在从事这方面的研究.理解生物时间节律的概念可以更好地预防、诊断和治疗人类癌症.我们邀请更多的中国医学科学研究人员和机构加入到我们这个研究行列,运用时间生物学的概念,为更有效地预防癌症、更早期地诊断癌症、更好地控制和治疗癌症而努力. | William J M Hrushesky Jovelyn Du-Quiton Masami Ohmori Patricia A.Wood | 2005 | 基础医学与临床2005，25，4： | 5 |
| 12 | National natural capital accounting with the ecological footprint concept显示文摘 | Mathis Wackernagel Larry Onisto Patricia Bello Alejandro Callejas Linares Ina Susana López Falfán Jesus Méndez Garc??a Ana Isabel Suárez Guerrero Ma Guadalupe Suárez Guerrero | 1999 | Ecological Economics1999，，3： | 5 |
| 13 | 利用经济学评价证据支持针灸医疗保险报销决策:现有证据及挑战显示文摘李洪超和同事们探索了在针灸医疗保险报销决策过程中引入经济学评价证据的全球挑战。医疗保险报销决策的过程本质上是复杂的。除了安全性和有效性,社会、经济、政治、地理、制度等非医学因素通常也会对决策制订产生重要的影响。 | 李洪超 金雪晶 Patricia M Herman Claudia M Witt 陈英耀 岗卫娟 景向红 宋坪 杨龙会 Dan Ollendorf 张渊 Gordon Guyatt 黄璐琦 张誉清(文/译) 王欣恬 | 2022 | 英国医学杂志中文版2022，25，6： | 5 |
| 14 | 中文版急性冠脉综合征反应指数量表信度及效度研究显示文摘目的:评价中文版急性冠脉综合征反应指数量表(C-ACSRI)的信度及效度。方法:采用翻译并修订的C-ACSRI对224例冠心病患者进行调查,并对结果进行信度、效度分析。结果:以Cronbach’sα系数检验总量表及态度、信念分量表的信度,Kuder-Rechardson 20(K-R20)系数检验知识分量表的信度,结果分别为0.81(总量表)、0.79(知识)、0.87(态度)、0.71(信念)。总量表的内容效度指数为0.93;分量表与总量表得分之间的相关系数为0.58~0.82,P<0.01;主成分分析经方差最大正交旋转后,知识分量表抽取2个因子共解释总方差的31.6%,态度、信念分量表抽取3个因子共解释总方差的61.0%。结论:中文版急性冠脉综合征反应指数量表具有良好的信度及效度,可作为临床医务人员和研究人员进行筛查、测量的工具。 | 曹英娟 曹秀玲 娄凤兰 高晖 刘庆红 Patricia M Davidson | 2013 | 中国护理管理2013，13，5： | 4 |
| 15 | 选择性环氧化酶2抑制剂和传统非甾体抗炎药增加粥样血栓形成的风险吗?随机试验的荟萃分析显示文摘目的:评价选择性环氧化酶2(COX-2)抑制剂和传统的非甾体类抗炎药(NSMDs)在发生血管事件上的风险性。设计:对已发表和未发表随机试验的表格式资料进行荟萃分析,对传统 NSAIDs 的作用进行间接评估。资料来源:资料分别来源于 Medline 和 Embase(1966年1月至2005年4月);食品与药品管理局记录;以及诺华、辉瑞、默克公司的资料。回顾方法:符合以下条件的随机试验入组本研究:一种选择性 COX-2抑制剂与安慰剂比较或一种选择性 COX-2抑制剂与一种传统的 NSAID之间对比;用药持续时间至少4周;包含严重血管事件方面的信息,如心肌梗死、卒中或由于血管事件死亡。各个独立研究者和药厂为本研究提供了有关随机化的病人数目、血管事件的数目以及每个随机化小组中随访的人时(Person time)等信息。结果:在与安慰剂对比的试验中,选择性COX-2抑制剂使严重血管事件发生率增加42%(1.2%/年比0.9%/年;率比1.42,95%可信区间1.13~1.78;P=0.005);不同的选择性 COX-2抑制剂之间没有显著性差异。这主要归因于心肌梗死的风险增加(0.6%/年比0.3%/年;1.86,1.33~2.59;P=0.0003),在其他血管性事件上没有明显的区别。在为时至少1年的试验中(平均2.7年),血管事件的率比是1.45(1.12~1.89;P=0.005)。总的来说,严重血管事件的发生率在选择性 COX-2抑制剂和任何传统 NSAID 之间没有差异(1.0%/年比0.9%/年;1.16,0.97~1.38;P=0.1)。然而,在选择性 COX-2抑制剂与萘普生对比的试验(1.57,1.21~2.03)和选择性COX-2抑制剂与非萘普生类 NSAIDs 相比较的试验之间(0.88,O.69~1.12),我们发现了统计学差异。与安慰剂比较血管事件的总体比率如下:萘普生0.92(0.67~1.26),布洛芬1.51(0.96~2.37),双氯芬酸1.63(1.12~2.37)。结论:选择性 COX-2抑制剂可以中等度增加血管事件的风险性,大剂量布洛芬和双氯芬酸同样具有此作用,但大剂量萘普生不明显增加血管事件的风险性。 | Patricia M Kearney Colin Baigent Jon Godwin Heather Halls Jonathan R Emberson Carlo Patrono 徐东(译) 张卓莉(校) | 2006 | 英国医学杂志中文版2006，9，5： | 4 |
| 16 | National natural capital accounting with the ecological footprint concept显示文摘 | Mathis Wackernagel Larry Onisto Patricia Bello Alejandro Callejas Linares Ina Susana López Falfán Jesus Méndez Garc??a Ana Isabel Suárez Guerrero Ma Guadalupe Suárez Guerrero | 1999 | Ecological Economics1999，，3： | 3 |
| 17 | Lactobacilli,bifi dobacteria and E.coli nissle induce pro-and anti-inflammatory cytokines in peripheral blood mononuclear cells显示文摘AIM: To investigate whether the stimulation of peripher- al blood mononuclear cells (PBMNC) with the cell debris and cell extraction of different probiotic strains is similar or species specifi c. METHODS: Three strains of bifi dobacteria, 4 strains of lactobacilli, and E. coli nissle were sonicated and centri- fuged in order to divide them into cell extract and cell debris. PBMNC were separated by density gradient and incubated for 36 h with either the cell debris or the cell extract of single strains of probiotic bacteria in doses from 102 to 108 CFU/mL. Cell supernatants were taken and interleukin (IL)-10, IL-1β, and tumor necosis factor (TNF)-α were determined by ELISA. RESULTS: Depending on the species super-family, the strains had different stimulation patterns. Except for both L. casei strains, the cell extract of bifidobacteriaand lactobacilli had less stimulating capacity than cell debris, whereas the cell extract of E. coli nissle had simi- lar stimulating properties to that of the cell debris of the strain and significantly more stimulating capacity than that of bifi dobacteria and lactobacilli. The cell debris of bifi dobacteria stimulated more cytokine release than the cell debris of lactobacilli. The cell debris of lactobacilli did not have a stimulating capacity when lower concentra- tions were used. Neither cell extraction nor cell debris had an inhibitory effect on the production of the tested cytokines by stimulated PBMNC. CONCLUSION: The incubation of probiotic strains, which have been used in clinical trials for inflammatory diseases, with immunocompetent cells leads to different species specifi c reactions. High IL-10 response to cell de- bris of bifi dobacteria and E. coli nissle can be found. This corresponds to positive effects of bifi dobacteria and E. coli nissle in clinical trials for inflammatory bowel disease compared to negative outcomes obtained with lactoba- cilli. | Ulf Helwig Karen M Lammers Fernando Rizzello Patricia Brigidi Verena Rohleder Elisabetta Caramelli Paolo Giochetti Juergen Schrezenmeir Ulrich R Foelsch Stefan Schreiber Massimo Campieri | 2006 | World Journal of Gastroenterology2006，12，37： | 3 |
| 18 | Lack of microRNA‐101 causes E‐cadherin functional deregulation through EZH2 up‐regulation in intestinal gastric cancer显示文摘 | Joana Carvalho Nicole C van Grieken Patricia M Pereira Sónia Sousa Marianne Tijssen Tineke E Buffart Bego?a Diosdado Heike Grabsch Manuel AS Santos Gerrit Meijer Raquel Seruca Beatriz Carvalho Carla Oliveira | 2012 | J Pathol2012，，1： | 3 |
| 19 | Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells显示文摘 | Patricia DA Lima Megan M Tu Mir Munir A Rahim Annie R Peng B Anne Croy Andrew P Makrigiannis | 2014 | Cellular & Molecular Immunology2014，11，5： | 3 |
| 20 | Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice(ob/ob)显示文摘AIM:To investigate the colocalization,density and profile of neuronal areas of enteric neurons in the ileum of male obese mice.METHODS:The small intestinal samples of male mice in an obese group(OG)(C57BL/6J ob/ob)and a control group(CG)(+/+)were used.The tissues were analyzed using a double immunostaining technique for immunoreactivity(ir)of the P2X2 receptor,nitric oxide synthase(NOS),choline acetyl transferase(ChAT)and calretinin(Calr).Also,we investigated the density and profile of neuronal areas of the NOS-,ChAT-and Calrir neurons in the myenteric plexus.Myenteric neurons were labeled using an NADH-diaphorase histochemical staining method.RESULTS:The analysis demonstrated that the P2X2receptor was expressed in the cytoplasm and in the nuclear and cytoplasmic membranes only in the CG.Neuronal density values(neuron/cm2)decreased 31%(CG:6579±837;OG:4556±407)and 16.5%(CG:7796±528;OG:6513±610)in the NOS-ir and calretininir neurons in the OG,respectively(P<0.05).Density of ChAT-ir(CG:6200±310;OG:8125±749)neurons significantly increased 31%in the OG(P<0.05).Neuron size studies demonstrated that NOS,ChAT,and Calr-ir neurons did not differ significantly between the CG and OG groups.The examination of NADH-diaphorase-positive myenteric neurons revealed an overall similarity between the OG and CG.CONCLUSION:Obesity may exert its effects by promoting a decrease in P2X2 receptor expression and modifications in the density of the NOS-ir,ChAT-ir and CalR-ir myenteric neurons. | Márcia Sanae Mizuno Amanda Rabello Crisma Primavera Borelli Bárbara Tavares Schfer Mariana Póvoa Silveira Patricia Castelucci | 2014 | World Journal of Gastroenterology2014，20，38： | 3 |
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