Transfusion of donor buffy coat cells in the treatment of persistent or recurrent malignancy after allogeneic bone marrow transplantation

BACKGROUND: Patients who experience relapse after allogeneic bone marrow transplantation have a poor prognosis. However, preclinical and clinical data have strongly suggested the existence of an immune- mediated anti-tumor effect of allogeneic bone marrow transplantation. This effect, termed graft-versus-leukemia, may be harnessed purposefully in patients with posttransplant relapses by the administration of immune cells obtained by leukapheresis of the original bone marrow donor. STUDY DESIGN AND METHODS: Thirteen patients with persistent or recurrent hematologic malignancy after HLA-matched sibling-donor allogeneic bone marrow transplantation were treated with transfusion of buffy coat cells collected from the original bone marrow donors. Mononuclear cell dose ranged from 1.18 to 4.28 × 10(8) per kg. Alpha-interferon (1.5-3 × 10(6) U/m2 3-5x/week) was given to seven patients. Patients were observed for the development of graft-versus- host disease and disease response. RESULTS: Three of five patients with chronic myelogenous leukemia had complete remissions. One of five patients with active acute leukemia attained complete remission. A sixth acute leukemia patient treated with buffy coat transfusion after the induction of remission with chemotherapy relapsed 12 months later. One patient with myeloma had a complete but transient response. A patient with Hodgkin's disease did not respond. Four patients remain in remission 4, 16, 17, and 29 months after attaining complete remission. Graft-versus-host disease occurred in eight patients, including all of those with a complete response. One patient developed transient pancytopenia. CONCLUSION: The transfusion of donor buffy coat cells has significant anti-tumor activity in patients with relapsed hematologic malignancy after allogeneic bone marrow transplantation. This effect is strongly associated with graft-versus-host disease.     

子宫内膜异位症与雌、孕激素受体及其亚型的相关性

子宫内膜异位症(EM)中异位内膜的生长和侵袭依赖于性激素,而性激素与其受体结合后才能起作用.该文综述了雌、孕激素受体的结构、功能、基因、亚型及其在在位、异位内膜中的表达,并探讨其在EM的发生、发展以及治疗和预后中的作用.     

Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats

BACKGROUND AND PURPOSE

Cannabinoid CB₁ receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB₁ receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.

EXPERIMENTAL APPROACH

The conditioned gaping model of nausea in rats was used to compare the CB₁ receptor antagonist/inverse agonist, AM251, and the CB₁ receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated.

KEY RESULTS

At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg·kg⁻¹) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg·kg⁻¹ of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.

CONCLUSIONS AND IMPLICATIONS

Inverse agonism, but not neutral antagonism, of CB₁ receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB₁ receptors, located distal to the cerebral ventricles.     

Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist

Background and purpose:

Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being Δ⁹-tetrahydrocannabinol, cannabidiol and Δ⁹-tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor.

Experimental approach:

The [³⁵S]GTPγS binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [³H]CP55940 from mouse CB₁ and human CB₂ cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.

Key results:

In the brain membrane experiments, cannabigerol behaved as a potent α₂-adrenoceptor agonist (EC₅₀= 0.2 nM) and antagonized the 5-HT_1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K_B= 51.9 nM). At 10 µM, it also behaved as a CB₁ receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be α₂-adrenoceptor-mediated (EC₅₀= 72.8 nM) and displayed significant affinity for mouse CB₁ and human CB₂ receptors.

Conclusions and implications:

This investigation has provided the first evidence that cannabigerol can activate α₂-adrenoceptors, bind to cannabinoid CB₁ and CB₂ receptors and block CB₁ and 5-HT_1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [³⁵S]GTPγS binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain.     

循证护理在心脏术后患者呼吸道管理中的应用

目的 探讨循证护理在心脏术后患者呼吸道管理中的应用效果.方法 通过运用循证护理,寻找兰州军区总医院心血管外科2009-06-2010-06心脏术后489例在临床实践中需要解决的护理问题,根据所提出的问题进行系统的文献查询,结合临床实践,对其有效性、实用性进行评估,并与常规方法相结合,得出有效的护理措施.结果 489例患者术后无呼吸系统并发症发生.结论 循证护理是以有价值的、可信的科学研究结果为依据,提出问题,寻找实证,用实证对心脏术后患者实施最佳护理,可提高心脏术后患者护理质量.     

重度子痫前期患者的体液因子与免疫细胞因子的相关性分析

目的 探讨重度子痫前期患者血浆中体液因子内皮素(ET)、血管紧张素Ⅱ(AngⅡ)和免疫细胞因子白介素-2( IL-2)、白介素-10(IL-10)、γ-干扰素(γ-IFN)和转化生长因子-β 1(TGF-β 1)在重度子痫前期发病中的意义及其相关性分析.方法 分别采用放射免疫法和双抗体夹心酶联免疫吸附测定法测定44例重度子痫前期孕妇(病例组),35例正常孕妇(对照组)妊娠晚期血浆中ET、AngⅡ和IL-2、IL-10、y-IFN、TGF-β 1水平.分析ET和AngⅡ与IL-2、IFN-γ、IL-10、TGF-β 1、IL-2/IL-10比值、IFN- γ/IL-10比值等各细胞因子之间的相关性.结果 ①病例组的血浆IL-2水平和血浆TGF-β 1水平高于对照组(P ＜0.001,P＜0.01);病例组的血浆IL-10水平低于对照组为,P＜0.001.②病例组血浆中IL-2/IL-10比值和IFN-γ/IL-10比值高于对照组(P＜0.001和P＜0.01).③病例组血浆中ET水平为高于对照组P＜0.01;病例组血浆中AngⅡ水平与对照组相比无显著差异P＞0.05.④病例组血浆ET水平与IL-2水平、IL-2/IL-1O比值、IFN-y/IL-10比值的相关性有显著的统计学意义,病例组的血浆AngⅡ水平与血浆IL-2水平相关性有显著的统计学意义(P＜0.01),病例组的血浆IL-10水平与血浆IFN-y水平相关性有统计学意义(P＜0.01).结论 免疫应答激活和免疫耐受不足共同参与了重度子痫前期的发生和发展,内皮细胞的损伤与免疫失衡相互协同促进了病程进展.     

Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy

Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to gamma-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy.     

层粘连蛋白、纤维粘连蛋白在胚胎发育中表达及作用

细胞外基质(ECM)主要分布于细胞外空间,包括胶原蛋白、非胶原蛋白和蛋白多糖三大类,在与其特殊黏附受体结合后,连接构成复杂的网架结构,起到调节组织发生和细胞生理活动的作用.层粘连蛋白(LN)、纤维粘连蛋白(FN)作为ECM的重要组成成分,广泛存在于各种动植物的细胞表面、细胞外液、结缔组织以及多数基底膜中.不仅在支持、连接和维持组织形态方面起重要作用,而且具有调节细胞黏附、生长、分化、促进细胞迁移、增殖、离子交换和信息传递的功能.对LN和FN的分子结构、合成分布及在胚胎着床、发育过程中表达与作用进行综述.     

A One-Stop Carpal Tunnel Clinic

INTRODUCTION

By December 2008, 90% of referrals requiring hospital admission will need to be seen and treated within the 18-week patient pathway. Previously, patients within our trust with suspected carpal tunnel syndrome had to wait 3 months to see a specialist in clinic and, once assessed, would have to wait up to a further 6 months for an open carpal tunnel decompression under local anaesthetic (OCTD/LA). We set up a one-stop clinic, where patients would have their out-patient consultation and surgery on the same day. We evaluated the clinic in order to assess whether it led to reduced waiting times whilst maintaining good clinical outcome and patient satisfaction.

PATIENTS AND METHODS

Patients were selected on the basis of the standard referral letter alone. Those selected were then assessed by a single surgeon in the clinic. The patients deemed appropriate underwent an OCTD/LA and were discharged the same day. Patients were followed up with a patient satisfaction and Boston questionnaire.

RESULTS

Forty-six patients underwent 63 OCTD/LA, waiting an average of 2.2 months (9 weeks) from referral. There was high patient satisfaction and improvement in symptoms following treatment in the clinic.

CONCLUSIONS

We believe a one-stop carpal tunnel clinic can be an efficient and cost-effective way of treating this common condition.     

Profiling proteasome activity in tissue with fluorescent probes

With proteasome inhibitors in use in the clinic for the treatment of multiple myeloma and with clinical trials in progress investigating the treatment of a variety of hematologic and solid malignancies, accurate methods that allow profiling of proteasome inhibitor specificity and efficacy in patients are in demand. Here, we describe the development, full biochemical validation, and comparison of fluorescent proteasome activity reporters that can be used to profile proteasome activities in living cells with high sensitivity. Seven of the synthesized probes tested label proteasomes in lysates, although the fluorescent dye used affects their specificity. Two differentially labeled probes tested are suitable for studying proteasome activity in living cells by gel-based assays, by confocal laser scanning microscopy, and by flow cytometry. We established methods using these fluorescent reporters to profile proteasome activity in different mouse tissues, carefully avoiding postlysis artifacts, and we show that proteasome subunit activity is regulated in an organ-specific manner. The techniques described here could be used to study in vivo pharmacological properties of proteasome inhibitors.