AML1-ETO阳性急性髓系白血病患者合并c-kit突变预后相关性总结

<正>急性髓系白血病(AML)是一组在临床及细胞遗传学上均具有高度异质性的综合征,是在多种致病因素作用下的造血干祖细胞遗传学变异累积的结果,细胞和分子遗传学异常是其致病基础。1973年Rowley等[1]首次提出t(8;21)(q22;q22)染色体易位,该易位可产生特异性的AML1-ETO融合基因,在AML的危险度分层中,AML1-ETO基因阳性是预后较好的一种遗传学异常,通过化疗可取得     

骨髓白血病细胞形态与AML1/ETO融合基因阳性的关系

t(8;21)(q22;q22)使21号染色体上的AML1基因与8号染色体上的ETO基因发生融合,形成AML1/ETO融合基因,产生一种嵌合蛋白,作为主要的抑制物改变了正常AML1-CBF(核结合因子)B这种与造血干细胞分化有关的转录复合物的生理功能,导致白血病的发生。急性髓细胞白血病(AML)部分成熟型的M2b亚型是我国学者于50年代末提出的,具有髓外浸润率高、治疗反应好、完全缓解率高、缓解期长等特点,其特异性遗传标志为8号与21号染色体的长臂在二区二带断裂并相互移位[t(8;21)(q22;q22)],AML1基因重排可作为诊断本病的分子标志。以往文献报导M2b出现AML1/ETO融合基因阳性率占95%以上,AML其他各亚型亦可出现,但极为少数。王平等报导AML1/ETO融合基因在M2b中占100%,AML1/ETO融合基因阳性AML在骨髓涂片中能检测到异形中幼粒细胞。肖志坚等总结30例AML1/ETO阳性病例M2b占26例。巩文玉等报道46例AML1/ETO融合基因阳性AMI患儿M2b仅占19.6%。笔者收集35例AML1/ETO融合基因阳性骨髓涂片标本,观察其白血病细胞形态,探讨细胞形态与AML1/ETO融合基因阳性的关系。     

急性白血病细胞遗传学改变与临床预后关系的探讨

目的应用细胞遗传学分析方法研究急性白血病(AL)染色体异常特征,结合临床评价细胞遗传学对AL诊治和判断预后的价值.方法采用直接法和短期培养法制备骨髓细胞染色体,并以R显带为主、G显带为辅对76例AL患者进行染色体核型分析,并观察疾病的诊治及转归情况.结果 76例急性白血病细胞核型异常检出率为 55%(42/ 76),初发病例异常核型31例,检出率61%(31/51),缓解病例异常核型5例,检出率31%(5/16);对52例患者随访中发现:核型正常16例,其中13例(81%)达缓解,2例(15%)复发;核型异常36例中22例(61%)达缓解,8例(36%)复发(P<0.05),核型正常组缓解率明显高于核型异常组,复发率明显低于核型异常组;核型正常、超二倍体及t(15;17)易位者疗效较好 ,而伴-7/7q-、t(9;22)、t(4;11)、t (9;11)、t(1;19)易位者疗效较差;缓解期染色体仍为异常核型者常复发,继发性染色体改变常预示病情恶化.结论半数以上AL患者可检出克隆性染色体异常且主要为特异性染色体重排,它们和特定的FAB亚型相关;细胞遗传学改变与预后的关系密切,是影响白血病预后的独立性因素.     

应用MICM分型联合检测t(8;21)AML

目的 :应用形态学、免疫学、细胞遗传学和分子生物学 (MICM)分型联合检测 t(8;2 1)急性髓细胞性白血病(AML ) ,以提高 t(8;2 1) AML的临床检出率和诊断准确率。方法 :以 4 5例 AML的初诊患者为研究对象 ,分别采用传统的骨髓细胞形态学观察和细胞化学染色进行 FAB分型 ;流式细胞术 (FCM)检测白血病细胞免疫表型 ;骨髓细胞短期培养法常规制备染色体标本 ,RHG显带技术进行核型分析 ;巢式 RT- PCR检测 AML 1- ETO融合转录本。结果 :4 7.1%以上的 t(8;2 1) AML患者有特征性的形态学改变 ,10 0 %的患者 93%以上的白血病细胞 MPO染色呈强阳性 ,t(8;2 1) AML主要见于 FAB- M2 ,但也可见于其他亚型 ;80 %的 t(8;2 1) AML患者伴有常规细胞遗传学可检测到的 t(8;2 1)易位 ;10 0 %的 t(8;2 1) AML患者 AML 1- ETO融合基因阳性 ;t(8;2 1) + 组 CD1 9、CD34 的表达及 CD1 9、CD34 的共表达率明显高于 t(8;2 1) - 组。结论 :t(8;2 1) AML 具有特征性的形态学、细胞遗传学、免疫学和分子生物学改变 ;应用 MICM分型联合检测 t(8;2 1) AML,能提高 t(8;2 1) AML 的检出率和诊断准确率 ,其中 ,采用巢式 RT-PCR检测 AML1- ETO融合转录本在 MICM分型中占有十分重要的地位     

急性白血病中MLL基因重排研究进展

MLL基因位于11号染色体长臂2区3带(11q23),是HOX基因转录的上游调节因子。研究显示,恶性血液病及拓扑异构酶Ⅱ抑制剂诱导均可导致MLL基因重排[3-4]。在急性白血病中常见MLL基因重排,其甚至作为急性白血病的标志之一。MLL重排阳性多见于急性髓细胞白血病(acute myeloblastic leukemia,AML)、急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)、骨髓增生异常综合征(myelodysplastic syndrome,MDS)及治疗相关性白血病。MLL基因重排在儿童AML中占14%,其中65%与婴儿AML相关;该重排基因在ALL中发病占6%,其中大约80%为婴儿(<1岁)ALL患者;该重排基因也常在MDS及经拓扑异构酶     

齐墩果酸诱导Kasumi-1细胞凋亡及对AML1-ETO表达的影响

目的 观察齐墩果酸(OA)诱导入急性髓系白血病M2型细胞株Kasumi-1凋亡及对AML1-ETO表达的影响.方法 用不同浓度OA作用于人急性髓系白血病M2型Kasumi-1细胞株,四氮唑蓝(MTT)法检测细胞增殖抑制率;Annexin V/PI双染色后,流式细胞仪检测细胞凋亡;Western blot法检测AML1-ETO蛋白表达水平;荧光原位杂交(Fish)检测融合基因AML1-ETO的变化.结果 OA以时间和剂量依赖方式抑制Kasumi-1细胞的增殖,24,48,72 h的IC50分别约为0.58,0.41,0.35 μmol·L-1.不同浓度(0.4,0.6,0.9μmol·L-1)OA作用24h后,细胞凋亡率明显增加,AML1-ETO蛋白表达下调.结论 OA对Kasumi-1细胞的抑制增殖和诱导凋亡作用可能与AML1-ETO的抑制有关.     

CBFβ-MYH11在急性粒单细胞白血病的表达及临床意义

<正>Inv(16)/t(16;16)形成了CBFβ-MYH11融合基因,CBFβ-MYH11基因与突变的KIT基因共同作用,在白血病发病过程中可能起重要作用[1]。Inv(16)/t(16;16)是急性髓系白血病(AML)较常见的染色体异常,占总AML患者的10%¹5%,最多见于M4Eo亚型[2]。因此,本研究采用荧光定量聚合     

非M3型急性髓系白血病细胞遗传学及分子生物学特征及预后分析

目的：探讨和分析非M3型急性髓系白血病（Acute myeloid leukemia, AML）细胞遗传学及分子生物学特征以及预后影响因素。方法：回归性分析我院99例非M3型初治AML患者临床及实验室数据,探讨和分析患者性别、年龄、初诊时白细胞数、血小板数、有无贫血、乳酸脱氢酶水平、染色体核型以及融合基因等因素对AML患者无疾病进展生存时间（Disease free survival, DFS）及总体生存时间（Overall survival, OS）的影响。结果：患者中位发病年龄为44岁（1-84）,中位随访时间为12.6月（0.33-59.47）,化疗后达完全缓解（complete remission, CR）率为62.7%,复发率为44.1%。不同年龄段患者CR率有明显差异（P=0.035）;单因素及多因素分析显示老年及染色体数目异常为AML患者OS的独立预后不良因素,t(8,21)/inv(16)系其独立预后良好因素。结论：老年及染色体数目异常为非M3型AML患者独立预后不良因素;t(8,21)/inv(16)是其独立预后良好因素。AML临床应结合年龄、细胞遗传学及分子生物学等预后因素进行预后评估,据此制定个体化治疗,对延长患者生存时间,提高生活质量,具有重要指导意义。     

伴t(8;21)急性髓系白血病的特征及预后因素分析

目的探讨伴t(8;21)急性髓细胞白血病的临床特征及预后影响因素。方法回顾分析50例我院伴有t(8;21)AML患者的临床特征,包括血象、细胞形态学、染色体、融合基因等,并分析预后影响因素。结果 50例患者中,男性32例,女性18例,平均中位年龄45岁,初诊时中位白细胞计数18.6×10~9/L,中位血红蛋白54 g/L,中位PLT 23×109/L。中位原始幼稚细胞54%。M2 45例(占90%),M5 3例(占6%),M4 2例(占4%)。32例(64%)为单纯t(8;21),无附加染色体异常,18例(36%)为具有附加染色体异常。21例行AML/ETO融合基因测定的病例中,21例均存在AML/ETO阳性。在18例进行c-kit基因测定中5例伴c-kit阳性,13例阴性。CR率90%。截止到随访日期,25例死亡(50%),25例存活(50%)。其中2年OS为60%,5年存活50%。结论性别、年龄、初诊时血红蛋白、血小板数、骨髓幼稚细胞比例等因素与预后无相关性。附加染色体、伴c-kit基因、初诊时白细胞数≥20×10~9/L是影响患者OS的不良预后因素,异基因造血干细胞移植可提高OS率。     

应用形态学、核型、免疫学和分子生物学方法联合检测急性髓细胞性白血病M_(2b)的研究

对20例急性髓细胞性白血病（AML）M2b亚型进行了形态学、免疫学、细胞遗传学和分子生物学方法（MICM）的联合检测。结果显示，形态学分型确诊率为90％（18／20），免疫学分析示80％（16／20）有髓系抗原表达，具有其典型特征者为40％（8／20）。染色体异常t（8；21）检出率为95％（19／20），采用RTPCR技术检测全部病例均显示AWL1－ETO融合基因阳性，提示在MICM联合诊断中，融合基因检测对AML－M2b的诊断，治疗及微小残留病监测有重要意义。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.