• 【功能性精子发生的发展需要生殖细胞凋亡的早期和大规模。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.9.2262 复制DOI
    作者列表:Rodriguez I,Ody C,Araki K,Garcia I,Vassalli P
    BACKGROUND & AIMS: Transgenic mice expressing high levels of the BclxL or Bcl2 proteins in the male germinal cells show a highly abnormal adult spermatogenesis accompanied by sterility. This appears to result from the prevention of an early and massive wave of apoptosis in the testis, which occurs among germinal cells during the first round of spermatogenesis. In contrast, sporadic apoptosis among spermatogonia, which occurs in normal adult testis, is not prevented in adult transgenic mice. The physiological early apoptotic wave in the testis is coincident, in timing and localization, with a temporary high expression of the apoptosis-promoting protein Bax, which disappears at sexual maturity. The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal mouse testis) in this early apoptotic wave is shown by the occurrence of a comparable testicular syndrome in mice defective in the bax gene. The apoptotic wave appears necessary for normal mature spermatogenesis to develop, probably because it maintains a critical cell number ratio between some germinal cell stages and Sertoli cells, whose normal functions and differentiation involve an elaborate network of communication.

    背景与目标: 在雄性生殖细胞中表达高水平BclxL或Bcl2蛋白的转基因小鼠表现出高度异常的成年精子发生并伴有不育。这似乎是由于防止了睾丸早期大量凋亡的结果,这种情况发生在第一轮精子发生过程中的生发细胞之间。相反,在成年转基因小鼠中,不能阻止正常成年人睾丸中发生的精原细胞中的偶发性细胞凋亡。睾丸中的生理性早期凋亡波在时间和位置上是一致的,具有促凋亡的蛋白Bax的临时高表达,该蛋白在性成熟时消失。 BclxL和Bax蛋白的细胞内平衡(可能是激素控制的)(在正常小鼠的睾丸中显然不表达Bcl2)在细胞内平衡中起着至关重要的作用,这是通过在小鼠体内出现类似的睾丸综合症而证明的。 bax基因。凋亡波似乎是正常成熟精子发生发展所必需的,这可能是因为它在某些生细胞阶段和支持细胞之间维持了关键的细胞数比,其正常功能和分化牵涉到复杂的交流网络。

  • 【N1-苄基-N2- [1-(1-萘基)乙基]-反式1,2-二氨基环己烷:4-氯苯基羧酰胺(calhex 231)的开发作为一种新型的钙感应受体配体,具有强大的钙分解活性。】 复制标题 收藏 收藏
    DOI:10.1021/jm051233+ 复制DOI
    作者列表:Kessler A,Faure H,Petrel C,Rognan D,Césario M,Ruat M,Dauban P,Dodd RH
    BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.
    背景与目标: :结构-活性关系(SAR)研究主要在N1-芳基磺酰基-N2- [1-(1-(萘基)乙基]-反式-1,2-二氨基环己烷的N1位置进行,钙敏感受体(CaSR)。该系列中活性最高的化合物是4-(三氟甲氧基)苯磺酰基衍生物7e,在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯([3H] IP)积累方面,其IC50为5.4 /-0.5 microM。表达CaSR的卵巢(CHO)细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍(7m,IC50 = 0.9 /-0.2 microM)。在合成的羧酰胺中,活性最高的化合物之一是4-氯苯基羧酰胺(1S,2S,1'R)-7n(Calhex 231,IC50 = 0.33 /-0.02 microM)。 (1S,2S,1'R)-7n的绝对构型是由化合物7d的一种非对映异构体的X射线晶体学研究得出的。 (1S,2S,1'R)异构体的立体化学偏好可以根据CaSR钙解结合口袋的三维模型来合理化。除去C-1'甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e,7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。
  • 【来自UT-7子系UT-7 / GM的红系和巨核细胞的体外发育。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Komatsu N,Kirito K,Shimizu R,Kunitama M,Yamada M,Uchida M,Takatoku M,Eguchi M,Miura Y
    BACKGROUND & AIMS: UT-7 is a human megakaryoblastic leukemia cell line with absolute dependence on interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin (EPO) for growth and survival. We isolated a novel subline, UT-7/GM after long-term culture of UT-7 with GM-CSF. The hemoglobin concentration and gamma-globin and EPO-receptor mRNA levels were significantly higher in EPO-treated UT-7/GM cells than in untreated cells. In contrast, the platelet factor 4 and glycoprotein IIb mRNA levels were much higher in thrombopoietin (TPO)-treated UT-7/GM cells than in untreated cells. Some TPO-treated cells had morphologically mature megakaryocytic characteristics such as a developed demarcation membrane in the cytoplasm and multilobular nuclei. These findings indicate that UT-7/GM is a bipotential cell line that can be induced to differentiate into erythroid and megakaryocytic lineages by EPO and TPO, respectively. Moreover, a minority of UT-7/GM cells acquired a high hemoglobin concentration by treatment with TPO, suggesting that TPO in part induced the erythroid differentiation of the UT-7/GM cells. Interestingly, GM-CSF inhibited the EPO- or TPO-induced erythroid differentiation and the TPO-induced megakaryocytic differentiation of UT-7/GM cells. These results support the hypothesis that cytokines influence the programming of gene expression required for lineage commitment or differentiation.

    背景与目标: UT-7是一种人类巨核细胞白血病细胞系,其绝对依赖白介素3,粒细胞巨噬细胞集落刺激因子(GM-CSF)或促红细胞生成素(EPO)来生长和存活。在将UT-7与GM-CSF长期培养后,我们分离出一个新的亚系UT-7 / GM。在EPO处理的UT-7 / GM细胞中,血红蛋白浓度,γ-珠蛋白和EPO受体mRNA水平显着高于未处理的细胞。相反,血小板生成素(TPO)处理的UT-7 / GM细胞中的血小板因子4和糖蛋白IIb mRNA水平比未处理的细胞高得多。一些用TPO处理过的细胞具有形态成熟的巨核细胞特征,例如在细胞质和多叶核中形成了分界膜。这些发现表明,UT-7 / GM是一种双能细胞系,可以被EPO和TPO分别诱导分化为红系和巨核细胞谱系。此外,少数UT-7 / GM细胞通过TPO处理获得了高血红蛋白浓度,这表明TPO部分诱导了UT-7 / GM细胞的类红细胞分化。有趣的是,GM-CSF抑制了EPO或TPO诱导的红系分化以及TPO诱导的UT-7 / GM细胞的巨核细胞分化。这些结果支持以下假设:细胞因子会影响谱系定型或分化所需的基因表达程序。

  • 【通过选择性阻断CD28预防NZB / NZW小鼠狼疮性肾炎的发展。】 复制标题 收藏 收藏
    DOI:10.1002/eji.201746923 复制DOI
    作者列表:Laurent L,Le Fur A,Bloas RL,Néel M,Mary C,Moreau A,Poirier N,Vanhove B,Fakhouri F
    BACKGROUND & AIMS: :Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.
    背景与目标: 系统性红斑狼疮(SLE)是一种慢性全身性炎症性疾病。通过自身反应性B细胞和CD4 T细胞之间的相互作用,产生并维持针对狼疮的标志性双链DNA(ds DNA)的自身抗体(autoAbs)。这种相互作用是由CD28 / CD80-86 / CTLA-4轴控制的。在这里,我们研究了CD28-CD80 / 86共刺激相互作用的选择性阻断是否消除了狼疮性肾炎在SLE鼠模型中的发展。为了这个目的,将NZB / NZW F1小鼠用抗CD28 Fab'片段或对照Fab'-IgG治疗3个月。评估了CD28阻断对狼疮肾炎发作,生存,抗ds DNA抗体产生和共刺激分子的影响。 CD28阻滞剂在3个月的治疗期间和12周后预防了狼疮性肾炎的发展并延长了生存期。此外,抗ds DNA autoAb的产生减少。最后,CD28阻断的保护作用与免疫调节分子吲哚胺2、3-二加氧酶,共抑制受体编程的细胞死亡-1(PD-1)及其配体编程的死亡配体的肾内表达增加有关。 -1(PDL-1)。总之,CD28阻断可预防NZB / NZW F1小鼠的狼疮性肾炎。这种免疫调节策略是人类SLE治疗的有希望的候选者。
  • 【蛋氨酸腺苷基转移酶2A在牛植入前发育及其相关基因组区域中的作用。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-04003-1 复制DOI
    作者列表:Ikeda S,Kawahara-Miki R,Iwata H,Sugimoto M,Kume S
    BACKGROUND & AIMS: :Methionine adenosyltransferase (MAT) is involved in folate-mediated one-carbon metabolism, which is essential for preimplantation embryos in terms of both short-term periconceptional development and long-term phenotypic programming beyond the periconceptional period. Here, our immunofluorescence analysis of bovine oocytes and preimplantation embryos revealed the consistent expression of MAT2A (the catalytic subunit of the ubiquitously expressed-type of MAT isozyme) during this period. Addition of the MAT2A inhibitor FIDAS to the culture media of bovine preimplantation embryos reduced their blastocyst development, revealing the particular importance of MAT2A in successful blastocyst development. Exploration of MAT2A-associated genomic regions in bovine blastocysts using chromatin immunoprecipitation and sequencing (ChIP-seq) identified candidate MAT2A-associated genes implicated not only in short-term periconceptional embryo development, but also in long-term phenotypic programming during this period in terms of growth, metabolism, and immune functions. These results suggest the critical involvement of MAT2A in the periconceptional period in life-long programming of health and disease as well as successful preimplantation development.
    背景与目标: :蛋氨酸腺苷基转移酶(MAT)参与叶酸介导的一碳代谢,这对于植入前的胚胎而言,无论是短期的受孕发育还是经过长期的表型编程,都是必不可少的。在这里,我们对牛卵母细胞和植入前胚胎的免疫荧光分析揭示了在此期间MAT2A(MAT酶的普遍表达型的催化亚基)的一致表达。在牛植入前胚胎的培养基中添加MAT2A抑制剂FIDAS可减少其胚泡发育,从而揭示MAT2A在成功的胚泡发育中特别重要。利用染色质免疫沉淀和测序(ChIP-seq)探索牛胚泡中与MAT2A相关的基因组区域,确定了与MAT2A相关的候选基因,不仅与短期围产期胚胎发育有关,而且与这一时期的长期表型编程有关。生长,新陈代谢和免疫功能。这些结果表明,MAT2A在整个生命周期的健康和疾病规划以及成功的植入前发展过程中,都处于围孕期的关键时期。
  • 【通过马拉维社区儿童保育中心改善儿童营养和发育-NEEP-IE研究:一项随机对照试验的研究方案。】 复制标题 收藏 收藏
    DOI:10.1186/s13063-017-2003-7 复制DOI
    作者列表:Gelli A,Margolies A,Santacroce M,Sproule K,Theis S,Roschnik N,Twalibu A,Chidalengwa G,Cooper A,Moorhead T,Gladstone M,Kariger P,Kutundu M
    BACKGROUND & AIMS: BACKGROUND:The Nutrition Embedded Evaluation Programme Impact Evaluation (NEEP-IE) study is a cluster randomised controlled trial designed to evaluate the impact of a childcare centre-based integrated nutritional and agricultural intervention on the diets, nutrition and development of young children in Malawi. The intervention includes activities to improve nutritious food production and training/behaviour-change communication to improve food intake, care and hygiene practices. This paper presents the rationale and study design for this randomised control trial. METHODS:Sixty community-based childcare centres (CBCCs) in rural communities around Zomba district, Malawi, were randomised to either (1) a control group where children were attending CBCCs supported by Save the Children's Early Childhood Health and Development (ECD) programme, or (2) an intervention group where nutritional and agricultural support activities were provided alongside the routine provision of the Save the Children's ECD programme. Primary outcomes at child level include dietary intake (measured through 24-h recall), whilst secondary outcomes include child development (Malawi Development Assessment Tool (MDAT)) and nutritional status (anthropometric measurements). At household level, primary outcomes include smallholder farmer production output and crop-mix (recall of last production season). Intermediate outcomes along theorised agricultural and nutritional pathways were measured. During this trial, we will follow a mixed-methods approach and undertake child-, household-, CBCC- and market-level surveys and assessments as well as in-depth interviews and focus group discussions with project stakeholders. DISCUSSION:Assessing the simultaneous impact of preschool meals on diets, nutrition, child development and agriculture is a complex undertaking. This study is the first to explicitly examine, from a food systems perspective, the impact of a preschool meals programme on dietary choices, alongside outcomes in the nutritional, child development and agricultural domains. The findings of this evaluation will provide evidence to support policymakers in the scale-up of national programmes. TRIAL REGISTRATION:ISRCTN registry, ID: ISRCTN96497560 . Registered on 21 September 2016.
    背景与目标: 背景:营养嵌入式评估计划影响评估(NEEP-IE)研究是一项集群随机对照试验,旨在评估基于托儿所的营养和农业综合干预对马拉维幼儿饮食,营养和发育的影响。干预措施包括改善营养食品生产的活动和培训/行为改变交流,以改善食物摄入,护理和卫生习惯。本文介绍了这项随机对照试验的原理和研究设计。
    方法:将马拉维Zomba地区周边农村社区的60个社区托儿中心(CBCC)随机分为(1)对照组,在该组中,儿童参加了由Save the Children's Early Childhood Health and Development(ECD)计划支持的CBCC,或(2)一个干预小组,在该小组的日常服务之外,还提供了营养和农业支持活动。儿童一级的主要结局包括饮食摄入量(通过24小时召回来衡量),而次级一级的结局包括儿童发育(马拉维发育评估工具(MDAT))和营养状况(人体测量)。在家庭一级,主要成果包括小农户的农产品产量和作物结构(回顾上个生产季节)。测量了沿理论化的农业和营养途径的中间结果。在此试验期间,我们将采用混合方法,并进行儿童,家庭,CBCC和市场级别的调查和评估,以及与项目利益相关者的深入访谈和焦点小组讨论。
    讨论:评估学龄前膳食对饮食,营养,儿童发育和农业的同时影响是一项复杂的工作。这项研究是第一个从食品系统的角度明确检查学龄前儿童饮食计划对饮食选择以及营养,儿童发育和农业领域的成果的影响的研究。评估的结果将为支持决策者扩大国家计划提供证据。
    试用注册:ISRCTN注册,ID:ISRCTN96497560。 2016年9月21日注册。
  • 【俄斯特拉发大学附属医院血液中心的粒细胞采集程序。】 复制标题 收藏 收藏
    DOI:10.5507/bp.2012.071 复制DOI
    作者列表:Cermakova Z,Blahutova S,Papajik T,Galuszkova D,Hubacek J,Sommerova M
    BACKGROUND & AIMS: BACKGROUND:Granulocyte apheresis is a safe and effective method for granulocyte collection. We present a five year experience (2006-2010) of the Blood Center, Faculty Hospital Ostrava, Czech Republic. Donor granulocyte transfusion is one treatment option for haemato-oncology patients with severe neutropenia complicated by bacterial/fungal infections unresponsive to standard antibiotic/antifungal treatment. In this study, we describe the experiences of the Blood Centre at the Faculty Hospital in Ostrava of granulocyte apheresis. METHODS AND RESULTS:A total of 149 granulocyte units were collected for 33 patients from the Department of Haemato-oncology, University Hospital Olomouc, over a 5-year period (2006-2010). Information on donor selection, laboratory screening, mobilization regimen and granulocyte yield was obtained and analyzed. All mandatory screening tests for infection markers, AB0 and Rh and abnormal erythrocyte antibodies were performed. The cytomegalovirus status of the donors was not investigated. Steroids were the only mobilization regimen used, and were generally well accepted. The mean granulocyte yield was 12.6×10(9)/per transfusion unit (range 5.4-30.3). All granulocyte concentrates were irradiated and transfused according to AB0 Rh compatibility within 24 h after collection. CONCLUSION:Based on our experience, granulocytapheresis is a safe and effective method for obtaining granulocytes but the yield can be significantly influenced by other variables. From the recipients' perspective, the use of donor granulocytes supports an effective therapeutic modality.
    背景与目标: 背景:粒细胞单采是一种安全有效的收集粒细胞的方法。我们介绍了捷克共和国俄斯特拉发学院医院血液中心的五年经验(2006-2010)。供体粒细胞输注是严重中性粒细胞减少症并发细菌/真菌感染而对标准抗生素/抗真菌治疗无反应的血液肿瘤患者的一种治疗选择。在这项研究中,我们描述了粒细胞单采的俄斯特拉发大学医院血液中心的经验。
    方法与结果:在5年期间(2006-2010年),从Olomouc大学医院血液肿瘤科收集了149粒粒细胞单位,用于33例患者。获得并分析了有关供体选择,实验室筛查,动员方案和粒细胞产量的信息。进行了所有感染标志物,AB0和Rh和异常红细胞抗体的强制性筛查测试。没有研究捐赠者的巨细胞病毒状况。类固醇是唯一使用的动员方案,并且普遍被接受。平均粒细胞产量为12.6×10(9)/每输血单位(范围5.4-30.3)。收集后24小时内,按照AB0 Rh相容性对所有粒细胞浓缩物进行辐照和输血。
    结论:根据我们的经验,粒细胞穿刺术是一种安全有效的获取粒细胞的方法,但产量会受到其他变量的显着影响。从接受者的角度来看,使用供体粒细胞支持有效的治疗方式。
  • 【肝移植后原发性硬化性胆管炎与溃疡性结肠炎相关的结肠癌的发展。】 复制标题 收藏 收藏
    DOI:10.1002/hep.1840110320 复制DOI
    作者列表:Higashi H,Yanaga K,Marsh JW,Tzakis A,Kakizoe S,Starzl TE
    BACKGROUND & AIMS: :Between February 26, 1981, and July 30, 1987, 36 patients underwent orthotopic liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Three of the 36 recipients died within 3 mo because of graft nonfunction or surgical complications. The other 33 (92%) lived for at least 1 yr. Two of the 33 died after 12 and 14 mo, respectively, of recurrent cholangiocarcinoma that was not diagnosed before transplantation. Four other patients died of recurrent liver failure (three cases) or immunoblastic sarcoma (one case) after 14, 21, 36 and 44 mo. Twenty-seven (75%) of the patients are still alive 23 to 81 mo after transplantation. Two patients have been diagnosed as having colorectal cancer 11 and 21 mo respectively, after transplantation, for an overall incidence of 5.6% (2 of 36) and a corrected incidence of 6.5% (2 of 31) if the three early deaths and two later deaths caused by cholangiocarcinomas are excluded. It is not known whether colorectal malignancies were present but undetected at the time of transplantation or whether they developed afterward. It is clear that patients who undergo liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis should have careful follow-up of the colon, including colonoscopy and multiple biopsies of the colorectal mucosa. Whether proctocolectomy should be considered prophylactically after liver transplantation is an unresolved issue.
    背景与目标: :1981年2月26日至1987年7月30日之间,因原发性硬化性胆管炎伴溃疡性结肠炎,对36例患者进行了原位肝移植。 36位接受者中有3位在3个月内死于移植物无功能或手术并发症。其余33名(92%)居住至少1年。 33例中有2例分别在移植前12个月和14个月后死于复发性胆管癌。在14、21、36和44个月后,另外四名患者死于复发性肝衰竭(三例)或免疫母细胞肉瘤(一例)。二十七(75%)位患者在移植后23到81 mo还活着。两名患者在移植后分别被诊断出患有大肠癌,分别为11和21 mo,总发病率为5.6%(36分之2),如果3例早期死亡和2例较晚死亡,则校正后的发病率为6.5%(31分2例)。胆管癌引起的死亡不包括在内。尚不知道是否存在大肠恶性肿瘤但在移植时未发现大肠恶性肿瘤或它们随后是否发展。显然,因原发性硬化性胆管炎与溃疡性结肠炎而进行肝移植的患者应仔细检查结肠,包括结肠镜检查和大肠黏膜多次活检。肝移植后是否应预防性考虑进行结肠直肠切除术尚未解决。
  • 【在晚期前列腺癌的早期药物开发中测试生物学假设的新策略。】 复制标题 收藏 收藏
    DOI:10.1373/clinchem.2012.185157 复制DOI
    作者列表:Ferraldeschi R,Attard G,de Bono JS
    BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.
    背景与目标: 背景:我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌(CRPC)治疗的新时代,最近5年中有5种新药显示出生存优势,并且数量惊人的有希望的新型药物进入临床。
    内容:我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略,不仅着眼于预测性和中间终点生物标志物的开发,还着重于新的假设检验,生物标志物驱动的临床试验设计。
    简介:随着一些有前途的药物进入临床,对CRPC进行药物开发的重新思考的压力越来越大,以确保对新型药物进行适当评估,并适当分配患者和资源。我们设想,通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试,生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。
  • 【香蕉MADS-box家族的全基因组分析与果实的发育和成熟密切相关。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03897-1 复制DOI
    作者列表:Liu J,Zhang J,Zhang J,Miao H,Wang J,Gao P,Hu W,Jia C,Wang Z,Xu B,Jin Z
    BACKGROUND & AIMS: :Proteins encoded by MADS-box genes are important transcription factors involved in the regulation of flowering plant growth and development. Currently, no systematic information exists regarding the MADS-box family in the important tropical fruit banana. Ninety-six MADS-box genes were identified from the banana (Pahang) A genome. Phylogenetic analysis indicated that Musa acuminata MCM1-AGAMOUS- DEFICIENS-SRF (MaMADS) could be divided into MIKCc, MIKC*, Mα/β and Mγ groups. MIKCc could be further divided into 11 subfamilies, which was further supported by conserved motif and gene structure analyses. Transcriptome analysis on the Feng Jiao (FJ) and BaXi Jiao (BX) banana cultivars revealed that MaMADS genes are differentially expressed in various organs, at different fruit development and ripening stages, indicating the involvement of these genes in fruit development and ripening processes. Interactive network analysis indicated that MaMADS24 and 49 not only interacted with MaMADS proteins themselves, but also interacted with hormone-response proteins, ethylene signal transduction and biosynthesis-related proteins, starch biosynthesis proteins and metabolism-related proteins. This systematic analysis identified candidate MaMADS genes related to fruit development and ripening for further functional characterization in plants, and also provided new insights into the transcriptional regulation of MaMADS genes, facilitating the future genetic manipulation of MADS-mediated fruit development and ripening.
    背景与目标: MADS-box基因编码的蛋白质是重要的转录因子,参与开花植物生长发育的调控。目前,在重要的热带水果香蕉中,尚无有关MADS盒家族的系统信息。从香蕉(彭亨州)A基因组中鉴定出96个MADS-box基因。系统发育分析表明,Musus acuminata MCM1-AGAMOUS-DEFICIENS-SRF(MaMADS)可以分为MIKCc,MIKC *,Mα/β和Mγ组。 MIKCc可以进一步分为11个亚家族,这由保守的基序和基因结构分析进一步支持。凤角(FJ)和八喜角(BX)香蕉品种的转录组分析表明,MaMADS基因在不同器官中处于不同的果实发育和成熟阶段差异表达,表明这些基因参与了果实发育和成熟过程。交互网络分析表明,MaMADS24和49不仅与MaMADS蛋白本身相互作用,而且还与激素响应蛋白,乙烯信号转导和生物合成相关蛋白,淀粉生物合成蛋白和代谢相关蛋白相互作用。这项系统分析确定了与果实发育和成熟有关的候选MaMADS基因,以进一步在植物中进行功能表征,也为MaMADS基因的转录调控提供了新见识,从而促进了MADS介导的果实发育和成熟的未来遗传调控。
  • 【术中神经监测变化清单的设计,开发和实施。】 复制标题 收藏 收藏
    DOI:10.3171/2012.9.FOCUS12263 复制DOI
    作者列表:Ziewacz JE,Berven SH,Mummaneni VP,Tu TH,Akinbo OC,Lyon R,Mummaneni PV
    BACKGROUND & AIMS: OBJECT:The purpose of this study was to provide an evidence-based algorithm for the design, development, and implementation of a new checklist for the response to an intraoperative neuromonitoring alert during spine surgery. METHODS:The aviation and surgical literature was surveyed for evidence of successful checklist design, development, and implementation. The limitations of checklists and the barriers to their implementation were reviewed. Based on this review, an algorithm for neurosurgical checklist creation and implementation was developed. Using this algorithm, a multidisciplinary team surveyed the literature for the best practices for how to respond to an intraoperative neuromonitoring alert. All stakeholders then reviewed the evidence and came to consensus regarding items for inclusion in the checklist. RESULTS:A checklist for responding to an intraoperative neuromonitoring alert was devised. It highlights the specific roles of the anesthesiologist, surgeon, and neuromonitoring personnel and encourages communication between teams. It focuses on the items critical for identifying and correcting reversible causes of neuromonitoring alerts. Following initial design, the checklist draft was reviewed and amended with stakeholder input. The checklist was then evaluated in a small-scale trial and revised based on usability and feasibility. CONCLUSIONS:The authors have developed an evidence-based algorithm for the design, development, and implementation of checklists in neurosurgery and have used this algorithm to devise a checklist for responding to intraoperative neuromonitoring alerts in spine surgery.
    背景与目标: 目的:本研究的目的是提供一种基于证据的算法,用于设计,开发和实施针对脊柱手术中对术中神经监测警报的反应的新清单。
    方法:对航空和外科文献进行了调查,以获取成功设计,开发和实施清单​​的证据。审查了清单的局限性以及实施清单的障碍。在此基础上,开发了神经外科检查清单创建和实现的算法。使用此算法,一个多学科团队调查了文献,以了解如何对术中神经监测警报做出反应的最佳实践。然后,所有利益相关者都对证据进行了审查,并就列入清单的项目达成了共识。
    结果:设计了对术中神经监测警报反应的清单。它强调了麻醉师,外科医生和神经监测人员的具体作用,并鼓励团队之间的沟通。它着重于对识别和纠正神经监测警报的可逆原因至关重要的项目。在初步设计之后,检查清单草稿经过了利益相关者的意见审查和修订。然后在小规模试验中对清单进行评估,并根据可用性和可行性进行修订。
    结论:作者开发了一种基于证据的算法,用于神经外科检查清单的设计,开发和实施,并已使用该算法设计了对脊柱手术中术中神经监测警报做出反应的检查清单。
  • 【在发育,再生和致癌过程中以及苯巴比妥治疗后,在大鼠肝脏中出现微粒体丁酸酯酶。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Kaneko A,Chisaka N,Enomoto K,Kaku T,Dempo K,Mori M,Onoe T
    BACKGROUND & AIMS: :A microsomal butyrylesterase (L-I) was purified from the livers of male W rats treated with phenobarbital, and an antiserum against this purified L-I was raised in a rabbit. By the Ouchteriony double-diffusion test, a precipitin line was observed between the anti-L-I antiserum and each Triton X-100 extract of livers during development, regeneration after partial hepatectomy, and carcinogenesis and of hyperplastic nodules and hepatomas, all of which revealed L-I in their esterase isoenzyme patterns. These precipitin lines exhibited esterase activity. The fusion of the lines of these tissue extracts and that of the purified L-I indicated the presence of an antigen site common to their esterases. The extracts of adult and fetal livers and also of hepatomas resembling fetal liver in the esterase isoenzyme pattern did not produce a precipitin line with anti-L-I antiserum.
    背景与目标: :从用苯巴比妥治疗的雄性W大鼠的肝脏中纯化微粒体丁酸酯酶(L-1),并在兔子中产生针对该纯化的L-1的抗血清。通过Ouchteriony双重扩散测试,在抗LI抗血清与肝脏的每个Triton X-100提取物之间的发育,部分肝切除术后的再生以及癌变以及增生性结节和肝癌的发展过程中,观察到一条沉淀蛋白线。它们的酯酶同工酶模式。这些沉淀素系表现出酯酶活性。这些组织提取物的线与纯化的L-1的线的融合表明存在其酯酶共有的抗原位点。在酯酶同工酶模式中,成年和胎儿肝脏的提取物以及类似于胎儿肝脏的肝瘤的提取物均未产生具有抗L-I抗血清的沉淀素。
  • 【在门诊诊所开发用于测量症状变化的量表。】 复制标题 收藏 收藏
    DOI:10.1016/0010-440x(90)90017-m 复制DOI
    作者列表:Plutchik R,Conte HR,Spence W,Buckley P,Karasu TB
    BACKGROUND & AIMS: :A brief 21-item symptom rating scale, the Psychiatric Outpatient Rating Scale (PORS), was developed for use in outpatient clinics. On the basis of its initial use with 86 patients, it was shown to have high internal and interjudge reliability and evidence of concurrent and construct validity. Scores on the PORS correlated significantly with the Global Assessment Scale and with the number of sessions of psychotherapy. For a subsample of 45 patients rated on the PORS at the beginning and termination of psychotherapy, seven symptoms revealed highly significant improvement. The PORS appears to be a potentially useful measure of change in outpatient clinics.
    背景与目标: :开发了一个简短的21个项目的症状评定量表,精神科门诊评定量表(PORS),用于门诊诊所。根据对86位患者的初次使用,它被证明具有很高的内部和法官间可靠性,以及并发和构建有效性的证据。 PORS的分数与全球评估量表以及心理疗法的疗程次数显着相关。对于在心理治疗开始和结束时接受PORS评估的45位患者的子样本,有7种症状显示出高度显着改善。 PORS似乎是门诊诊所变化的潜在有用措施。
  • 【发出通知前的传单以鼓励初次接受宫颈筛查的患者:定性研究。】 复制标题 收藏 收藏
    DOI:10.1093/her/cys103 复制DOI
    作者列表:Sadler L,Albrow R,Shelton R,Kitchener H,Brabin L
    BACKGROUND & AIMS: :Cervical screening attendance among women aged 25-29 years in England is lower than at older ages. There is some evidence that pre-notification leaflets motivate women who have not yet considered their response to a health intervention. We aimed to identify key information to motivate young women at their first cervical screening invitation. Six focus groups were conducted, five with young women aged 17-25 registered with a General Practice in Manchester, UK, and one with Practice nurses. Some women took part in two further groups to discuss leaflet design. There was low awareness of the purpose or procedures of cervical screening, and most women were de-motivated by reports of bad experiences. Some intended to be screened, but not immediately after invitation. Screening was viewed as a test for a cancer that affected older women. Since none of the participants believed that they had cervical cancer, screening seemed unnecessary. We conclude that the perception that screening is unimportant when you are young needs to be challenged. Women also need to be better informed of screening procedures. A pre-notification leaflet incorporating key information was designed and will be tested in a randomized trial of complex interventions within the routine cervical screening programme.
    背景与目标: :在英格兰,年龄在25-29岁之间的女性接受子宫颈筛查的比例低于年龄较大的女性。有证据表明,预先通知传单可以激励尚未考虑其对健康干预措施反应的妇女。我们旨在识别关键信息,以激发年轻女性的首次宫颈筛查邀请。进行了六个焦点小组讨论,其中五个在17-21岁的年轻女性中注册了英国曼彻斯特的General Practice,一个在执业护士中进行。一些妇女参加了另外两个小组,讨论传单设计。人们对宫颈筛查的目的或程序认识不足,大多数妇女因不良经历的报道而失去动力。有些打算放映,但不是在邀请后立即放映。筛查被认为是对影响老年妇女的癌症的测试。由于没有一个参与者相信自己患有宫颈癌,因此筛查似乎是不必要的。我们得出的结论是,对年轻时进行筛查并不重要的看法需要受到挑战。还需要使妇女更好地了解筛查程序。设计了包含关键信息的预告传单,并将在常规宫颈筛查计划内的复杂干预措施的随机试验中进行测试。
  • 【植物发育的实时成像:最新方法。】 复制标题 收藏 收藏
    DOI:10.1016/j.pbi.2012.10.006 复制DOI
    作者列表:Sappl PG,Heisler MG
    BACKGROUND & AIMS: :Development is a dynamic process occurring at the microscopic scale. The ability to see how it unfolds in detail is invaluable not only for helping us appreciate its full complexity but also to experimentally dissect its mechanisms. The sophistication of experimental approaches and imaging technologies has increased over the past decade at an astounding pace. In this review we highlight and discuss several studies that illustrate the latest advances in the application of live-imaging to dissect plant development.
    背景与目标: :发展是发生在微观尺度上的一个动态过程。了解它如何详细展现的能力非常宝贵,不仅有助于我们了解它的全部复杂性,而且还可以通过实验来剖析其机制。在过去的十年中,实验方法和成像技术的复杂性以惊人的速度增长。在这篇综述中,我们重点介绍并讨论了一些研究,这些研究说明了将实时成像技术应用于解剖植物发育的最新进展。

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