伊马替尼治疗Ph阳性进展期慢性粒细胞白血病

目的:观察伊马替尼治疗Ph阳性进展期慢性粒细胞白血病(CML)的疗效和耐药情况,研究改善伊马替尼耐药的方法。方法:32例Ph阳性进展期CML病人,其中加速期12例,急变期20例,每日口服伊马替尼600或800mg,持续3～9mo。结果:CML加速期病人血液学完全缓解率和总有效率分别为42%和83%,主要细胞遗传学缓解率25%,持续完全血液学缓解病例占25%。CML急变期各类型病人血液学完全缓解率和总有效率分别为20%和55%,主要细胞遗传学缓解率15%,持续完全血液学缓解病例占10%。CML急变期原发耐药和继发耐药分别为45%和20%,联合化疗与暂停伊马替尼对继发耐药可暂时改善其耐药性,但药物有效时间明显缩短。结论:伊马替尼对初治或复治的CML加速期和急变期病人均有效,可作为非移植CML治疗的标准一线方案,伊马替尼治疗CML急变期的原发耐药和继发耐药率较高,联合化疗和暂停伊马替尼可暂时改善其耐药性。     

小剂量伊马替尼治疗慢性髓细胞白血病急变期患者的临床疗效

目的　评价小剂量伊马替尼治疗慢性髓细胞白血病急变期 (CML -BC)的有效性和安全性。方法　 8例经α -干扰素、羟基脲联合治疗 (部分结合阿糖胞苷 )发生急变的CML患者 ,口服伊马替尼 2 0 0～ 30 0mg·d-1,维持治疗 18～ 94周。结果　血液学完全缓解 4例 ,部分缓解 2例。细胞遗传学主要缓解 2例 ,改善 2例。不良反应少且耐受好。结论　小剂量伊马替尼对α-干扰素、羟基脲等联合治疗失败的CML -BC具有较好的近期血液学和细胞遗传学效应 ,远期疗效有待进一步观察。     

伊马替尼治疗儿童慢性粒细胞白血病发生急淋变2例报告及文献复习

目的探讨伊马替尼治疗儿童慢性粒细胞白血病(CML)过程中发生急淋变的治疗经验。方法 纳入安徽省肿瘤医院2015年8月及2016年6月收住的2例儿童CML口服伊马替尼治疗过程中发生急淋变病人,统计达到血液学反应(CHR)时间、定期复查骨髓细胞学及融合基因、染色体。确定儿童CML急淋变后予以“达沙替尼+改良VDLP” 方案化疗,骨髓缓解后积极行异基因造血干细胞移植(HSCT)。结果 2例病人分别于口服伊马替尼后第18天及第33天达到CHR,1年后Ph染色体均未转阴,且发生急淋变。确定儿童CML急淋变后予以“达沙替尼+改良VDLP” 方案化疗,骨髓均得到缓解,2例HSCT均顺利完成。结论 伊马替尼治疗儿童CML过程中发生急淋变后,予以改用达沙替尼及改良VDLP方案化疗,并予以HSCT,患儿预后良好。     

伊马替尼联合三氧化二砷治疗进展期慢性粒细胞性白血病疗效观察

目的观察伊马替尼联合三氧化二砷治疗慢性粒细胞性白血病（CML）进展期的疗效和安全性。方法20例CML患者均予伊马替尼联合三氧化二砷治疗,常规体检,用药后血液学取得完全缓解后择期复查骨髓、Ph染色体和（或）bcr／abl基因。结果随访结束时,血液学完全缓解率20％（4／20）,部分缓解率25％（5／20）,总有效率45％,绝大多数为轻度不良反应,多可耐受。结论伊马替尼联合三氧化二砷治疗进展期CML有效、安全,但远期疗效需进一步观察。     

伊马替尼治疗慢性粒细胞性白血病的疗效观察

目的探讨伊马替尼治疗慢性粒细胞性白血病的近期疗效和安全性。方法应用伊马替尼400～600mg·d-1顿服治疗不同时期的慢性粒细胞性白血病患者18例,评价治疗后的临床疗效和不良反应的发生情况。结果 18例CML患者中11例患者达血液学完全缓解,占61.11%,2例患者血液学部分缓解,总体有效率达到72.22%,临床受益率达83.33%。所有患者均出现一种或多种不良反应,主要包括粒细胞及血小板减少(16.67%)、胃肠道反应(38.89%)、全身水肿(27.78%)、肌肉疼痛或痉挛(33.33%)、低热(16.67%)、皮疹(11.11%)。结论伊马替尼治疗CML患者的近期疗效好,且不良反应轻,可作为无法接受骨髓移植治疗的CML患者的首选化疗药物,但其远期临床疗效尚有待于进一步研究阐明。     

甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞性白血病的临床疗效观察

目的:探讨甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞白血病的临床疗效及不良反应情况。方法:对我院近年来应用甲磺酸伊马替尼治疗的29例晚期慢性粒细胞白血病患者的临床资料进行回顾性分析,并记录治疗过程中各时间点血常规、骨髓细胞形态学检查、细胞遗传学检查情况,对临床疗效及不良反应进行评价。结果:急变期CML患者血液学缓解率为28.6%,完全细胞遗传学缓解率为0,均明显低于加速期CML患者的73.3%和26.7%,差异均有统计学意义。治疗过程中血液学不良反应主要以白细胞,血小板减少多主,非血液学不良反应可有恶心、呕吐、水肿、骨骼肌酸痛、乏力、头昏、头痛、皮疹等。结论:甲磺酸伊马替尼治疗慢性粒细胞白血病加速期急变期患者疗效好,不良反应少,可耐受且加速期疗效优于急变期。     

Bcr-Abl激酶抑制剂尼罗替尼的药理与临床评价

慢性粒细胞性白血病(CML)和费城染色体阳性急性淋巴细胞白血病(Ph ALL),是由Bcr-Abl癌基因引起的.伊马替尼能抑制Bcr-Abl蛋白酪氨酸激酶活性,是一种有效的治疗慢性期CML的药物,但由于其耐药点突变,使加速期或急变期CML和Ph ALL患者常常复发.尼罗替尼是第2代Bcr-Abl激酶抑制剂,效果比伊马替尼强20倍,对伊马替尼耐药和不能耐受的患者(T3151除外)有广泛的活性.Ⅰ/Ⅱ期临床试验表明,尼罗替尼对伊马替尼耐药或不能耐受的CML患者仍能获得血液学和细胞遗传学的缓解.现对尼罗替尼的药理作用、药动学、药物相互作用、安全性进行综述.     

新型抗肿瘤药物依曼替尼布

依曼替尼布是一种新型的 2 苯胺基嘧啶类酪氨酸激酶抑制药 ,用于α 干扰素治疗失败后的慢性髓样白血病 (CML)慢性期病人、加速期病人、急变期病人的治疗。临床研究表明该药对病人血液学缓解及主要细胞分化缓解显著     

伊马替尼与干扰素联合治疗慢性粒细胞白血病的疗效分析

目的:探讨伊马替尼与干扰素联合化疗治疗慢性粒细胞白血病(CM L)的疗效。方法:2004年6月—2009年7月新诊断的58例Ph染色体阳性CM L慢性期患者,随机分为伊马替尼组和干扰素联合化疗组,比较两组临床疗效。结果:两组总有效率差异无统计学意义(P>0.05);伊马替尼组完全血液学缓解率,完全细胞遗传学缓解率、完全分子学效应率、5年总生存率均明显高于干扰素联合化疗组(P<0.05)。结论:伊马替尼和干扰素联合化疗都可作为CM L慢性期的有效治疗方法,应依据不同情况实施个体化治疗。     

伊马替尼联合化疗治疗Ph加急性淋巴细胞白血病

目的探讨伊马替尼联合化疗治疗ph /bcr-abl 急性淋巴细胞性白血病(ALL)的疗效。方法ph ALL患者12例,应用VDCP或VDCLP方案联合伊马替尼诱导治疗,完全缓解后伊马替尼与化疗交替进行巩固及强化治疗。结果12例ph ALL完全缓解(CR)9例。总CR率75%。无治疗相关死亡。9例CR患者化疗与伊马替尼交替进行巩固及强化治疗,中位缓解期11(7～19)个月。结论伊马替尼联合化疗治疗Ph ALL,CR率较常规化疗诱导治疗明显提高。化疗与伊马替尼交替进行巩固治疗,中位缓解时间及生存时间也较单用化疗明显延长。     

Bcl-2抑制剂用于急性髓系白血病靶向治疗的研究进展

摘要： 急性髓系白血病 （AML） 是成人最常见的急性白血病, 诱导化疗仍是AML的一线治疗手段。但是, 由于 AML诱导化疗毒性较高, 且有高失败率及高复发率的特点, 在AML患者中应用受限。近年来, 去甲基化药物地西他滨和阿扎胞苷在AML表观遗传学治疗中得到深入研究, 已经动摇了诱导化疗在AML治疗中的地位。随着对AML生物学研究的深入, 发现越来越多的靶点可影响AML的生物学进程。针对这些靶点的靶向药物分为3类： 第一类是突变位点抑制剂, 如FLT3和IDH抑制剂; 第二类是调节代谢或信号通路的抑制剂, 如Bcl-2拮抗剂及表观遗传学药物;第三类是靶向细胞毒性药物。2017年美国血液学年会报道, AML靶向治疗最有前景的药物为调节代谢或信号通路的抑制剂, 其中BCL-2抑制剂Venetoclax在AML的临床试验报告被评为本届会议最佳。本文就BCL-2抑制剂在 AML的治疗进展做一综述。     

Differential effect of L-NAME and S-methyl-isothiourea on leukocyte emigration in carrageenin-soaked sponge implants in rat

1. The role of nitric oxide (NO) in leukocyte (polymorphonuclear cells, monocytes and lymphocytes) emigration was studied in a model of carrageenin-sponge implants in rats.
2. The subcutaneous implantation of 1% (w/v) of λ-carrageenin-soaked sponges elicited an inflammatory response that was characterized by a time-related increase in leukocyte infiltration in the sponges and increased levels of nitrite in the exudate. Total leukocyte infiltration and nitrite production were maximal at 24 h and decreased after 48 and 96 h. The mononuclear cell influx was maximal at 48 h (21% of the total leukocytes). Therefore, this time point was used in the successive experiments.
3. Polymorphonuclear cell (PMN) and lymphocyte infiltration in the sponges significantly increased when rats were treated with the non-specific NO-synthase (NOS) inhibitor, N^G-nitro-L-arginine methylester (L-NAME) (1 mg ml⁻¹ in drinking water ad libitum). Monocyte emigration was not affected by L-NAME treatment. The nitrite levels in the exudate of L-NAME-treated rats were significantly reduced. The concomitant ingestion of L-arginine (30 mg ml⁻¹) resulted in a reversion of the L-NAME effect, while D-arginine (30 mg ml⁻¹) had no effect, indicating the involvement of the L-arginine: NO pathway.
4. Administration of L-NAME resulted also in an increased release of tumour necrosis factor-α (TNF-α) and prostacyclin (measured as the stable metabolite, 6-keto-PGF_1α). L-NAME had no effect on monocyte chemoattractant protein-1 (MCP-1) release in the exudate.
5. Since L-NAME may have effects on the local blood flow, phenylephrine (0.034 mg ml⁻² in drinking water) was used as it has an effect on the local blood flow similar to L-NAME. Phenylephrine had no effect on either leukocyte emigration, or on nitrite, TNF-α, prostacyclin or MCP-1 accumulation in the exudate.
6. In contrast, the more selective iNOS inhibitor S-methyl-isothiourea (SMT) (10 μg ml⁻¹ in drinking water) significantly reduced PMNs and lymphocyte influx in the sponge, having no effect on monocyte influx. Moreover, SMT decreased nitrite production in the exudate to a comparable extent as L-NAME.
7. Administration of SMT significantly reduced MCP-1 release in the exudate, without an effect on TNF-α or prostacyclin production. Moreover SMT did not produce any changes in local blood flow.
8. Our results show that a different outcome of the inflammatory process can be obtained depending on the types of NOS inhibitor used.

     

黄酮类化合物抗卵巢癌化疗耐药的作用进展

摘要：黄酮类化合物是广泛存在于自然界的一类多酚类物质,亦是诸多传统中草药中的有效成分之一,因其高效、低毒,且具有多种生物学活性而得到了广泛的关注。卵巢癌是病死率最高的妇科恶性肿瘤,化疗耐药是导致其预后不良的主要原因之一。研究发现,黄酮类化合物对改善卵巢癌耐药有独特的效果,或将有助于克服卵巢癌耐药。本文就近年来黄酮类化合物改善卵巢癌化疗耐药作用的相关研究进展进行综述。     

Lipids and lipidomics in brain injury and diseases

Lipidomics is systems-level analysis and characterization of lipids and their interacting moieties. The amount of information in the genomic and proteomic fields is greater than that in the lipidomics field, because of the complex nature of lipids and the limitations of tools for analysis. The main innovation during recent years that has spurred advances in lipid analysis has been the development of new mass spectroscopic techniques, particularly the "soft ionization" techniques electrospray ionization and matrix-assisted laser desorption/ionization. Lipid metabolism may be of particular importance for the central nervous system, as it has a high concentration of lipids. The crucial role of lipids in cell signaling and tissue physiology is demonstrated by the many neurological disorders, including bipolar disorders and schizophrenia, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick diseases, that involve deregulated lipid metabolism. Altered lipid metabolism is also believed to contribute to cerebral ischemic (stroke) injury. Lipidomics will provide a molecular signature to a certain pathway or a disease condition. Lipidomic analyses (characterizing complex mixtures of lipids and identifying previously unknown changes in lipid metabolism) together with RNA silencing, using small interfering RNA (siRNA), may provide powerful tools to elucidate the specific roles of lipid intermediates in cell signaling and open new opportunities for drug development.     

Adaptive changes in autophagy after UPS impairment in Parkinson's disease

Aim:

Ubiquitin-proteasome system (UPS) and autophagosome-lysosome pathway (ALP) are the most important machineries responsible for protein degradation in Parkinson''s disease (PD). The aim of this study is to investigate the adaptive alterations in autophagy upon proteasome inhibition in dopaminergic neurons in vitro and in vivo.

Methods:

Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 μmol/L) for 5, 12, or 24 h. The expression of autophagy-related proteins in the cells was detected with immunoblotting. UPS-impaired mouse model of PD was established by microinjection of lactacystin (2 μg) into the left hemisphere of C57BL/6 mice that were sacrificed 2 or 4 weeks later. The midbrain tissues were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays.

Results:

Both in SH-SY5Y cells and in the midbrain of UPS-impaired mouse model of PD, treatment with lactacystin significantly increased the expression levels of LC3-I/II and Beclin 1, and reduced the levels of p-mTOR, mTOR and p62/SQSTM1. Furthermore, lactacystin treatment in UPS-impaired mouse model of PD caused significant loss of TH-positive neurons in the substantia nigra, and dramatically increased the number of autophagosomes in the left TH-positive neurons.

Conclusion:

Inhibition of UPS by lactacystin in dopaminergic neurons activates another protein degradation system, the ALP, which includes both the mTOR signaling pathway and Beclin 1-associated pathway.     

Zoledronic acid induces formation of a pro-apoptotic ATP analogue and isopentenyl pyrophosphate in osteoclasts in vivo and in MCF-7 cells in vitro

Background and purpose:

Bisphosphonates (BPs) are highly effective inhibitors of bone resorption. Nitrogen-containing bisphosphonates (N-BPs), such as zoledronic acid, induce the formation of a novel ATP analogue (1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester triphosphoric acid; ApppI), as a consequence of the inhibition of farnesyl pyrophosphate synthase and the accumulation of isopentenyl pyrophosphate (IPP). ApppI induces apoptosis, as do comparable metabolites of non-nitrogen-containing bisphosphonates (non-N-BPs). In order to further evaluate a pharmacological role for ApppI, we obtained more detailed data on IPP/ApppI formation in vivo and in vitro. Additionally, zoledronic acid-induced ApppI formation from IPP was compared with the metabolism of clodronate (a non-N-BP) to adenosine 5′(β,γ-dichloromethylene) triphosphate (AppCCl₂p).

Experimental approach:

After giving zoledronic acid in vivo to rabbits, IPP/ApppI formation and accumulation was assessed in isolated osteoclasts. The formation of ApppI from IPP was compared with the metabolism of clodronate in MCF-7 cells in vitro. IPP/ApppI and AppCCl₂p levels in cell extracts were analysed by mass spectrometry.

Key results:

Isopentenyl pyrophosphate/ApppI were formed in osteoclasts in vivo, after a single, clinically relevant dose of zoledronic acid. Furthermore, exposure of MCF-7 cells in vitro to zoledronic acid at varying times and concentrations induced time- and dose-dependent accumulation of IPP/ApppI. One hour pulse treatment was sufficient to cause IPP accumulation and subsequent ApppI formation, or the metabolism of clodronate into AppCCl₂p.

Conclusions and implications:

This study provided the first conclusive evidence that pro-apoptotic ApppI is a biologically significant molecule, and demonstrated that IPP/ApppI analysis is a sensitive tool for investigating pathways involved in BP action.     

单克隆抗体制备技术研究进展

 抗体药物的开发离不开抗体制备技术。随着分子生物学和二代测序技术的发展以及流式细胞分选技术的广泛应用,抗体制备技术也得以不断发展。此文概述了鼠杂交瘤技术、噬菌体展示技术、转基因小鼠技术等经典的单克隆抗体制备技术,重点介绍了新兴的单细胞逆转录PCR技术。     

Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF-kappaB pathway

BACKGROUND AND PURPOSE: Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Ethanol (EtOH) reduces host defence systems, including cell adhesion. However, well-known side effects of EtOH limit its clinical use as an anti-inflammatory drug. Instead, ethyl pyruvate (EtP) may represent a better alternative. Here, we compared effects of EtP and EtOH on neutrophil recruitment and activation of human umbilical vein endothelial cells (HUVECs). EXPERIMENTAL APPROACH: Adhesion of neutrophils to HUVEC monolayers, surface expression of intercellular cell adhesion molecule, E-selectin, vascular cell adhesion molecule, release of interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) from HUVECs were assessed as well as translocation of interleukin-1 receptor-associated kinase (IRAK-1), the nuclear factor-kappa B (NF-kappaB) subunits p50, p65 and IkappaB-alpha. NF-kappaB activation was analysed with a luciferase reporter plasmid. Cells were stimulated with IL-1beta, lipopolysaccharide (LPS) or tumour necrosis factor-alpha.Key results:EtP was several-fold more potent than EtOH in reducing adhesion of neutrophils to activated HUVECs, generation of IL-8 or G-CSF and surface expression of the adhesion molecules. This last reaction was decreased by EtP even when added after cytokines or LPS. Translocation of IRAK-1, IkappaBalpha and the NF-kappaB p65 subunit to the HUVEC nucleus was inhibited by EtP for all stimuli, whereas the diminished p50 translocation was stimulus specific. When p65 was constitutively expressed in Cos7 cells, stimulation of an NF-kappaB-dependent reporter gene was not affected by EtP, suggesting that EtP acted upstream of gene activation. CONCLUSIONS AND IMPLICATIONS: EtP impedes adhesive, secretory and signalling events typical of the early inflammatory response in endothelial cells, suggesting EtP as a possible treatment for acute inflammatory conditions.     

Roles of proteolysis in regulation of GPCR function

The enzymatic activity of peptidases must be tightly regulated to prevent uncontrolled hydrolysis of peptide bonds, which could have devastating effects on biological systems. Peptidases are often generated as inactive propeptidases, secreted with endogenous inhibitors, or they are compartmentalized. Propeptidases become active after proteolytic removal of N-terminal activation peptides by other peptidases. Some peptidases only become active towards substrates only at certain pHs, thus confining activity to specific compartments or conditions. This review discusses the different roles proteolysis plays in regulating GPCRs. At the cell-surface, certain GPCRs are regulated by the hydrolytic inactivation of bioactive peptides by membrane-anchored peptidases, which prevent signalling. Conversely, cell-surface peptidases can also generate bioactive peptides, which directly activate GPCRs. Alternatively, cell-surface peptidases activated by GPCRs, can generate bioactive peptides to cause transactivation of receptor tyrosine kinases, thereby promoting signalling. Certain peptidases can signal directly to cells, by cleaving GPCR to initiate intracellular signalling cascades. Intracellular peptidases also regulate GPCRs; lysosomal peptidases destroy GPCRs in lysosomes to permanently terminate signalling and mediate down-regulation; endosomal peptidases cleave internalized peptide agonists to regulate GPCR recycling, resensitization and signalling; and soluble intracellular peptidases also participate in GPCR function by regulating the ubiquitination state of GPCRs, thereby altering GPCR signalling and fate. Although the use of peptidase inhibitors has already brought success in the treatment of diseases such as hypertension, the discovery of new regulatory mechanisms involving proteolysis that control GPCRs may provide additional targets to modulate dysregulated GPCR signalling in disease.     

子宫肌瘤并发淀粉样变患者发病机制研究

摘要： 目的 探讨子宫肌瘤并发淀粉样变患者发病机制。方法 子宫肌瘤患者 36 例。依据组织病理刚果红（CR） 染色结果分为淀粉样变组 6 例和非淀粉样变组 30 例。（1） 观察淀粉样变组淀粉样变沉积部位。（2） HE 染色比较 2 组炎性细胞浸润情况。（3） PAS 染色观察淀粉样变组多糖类物质沉积的变化。（4） 比较 2 组血红蛋白 （HGB）、 白细胞计数 （WBC）、 淋巴细胞绝对值 （LYM）、 中性粒细胞绝对值 （NEU）、 总蛋白 （TP）、 白蛋白 （Alb） 及前白蛋白 （PA） 的含量。结果 （1） 肌瘤实体纤维细胞间质未见淀粉样变, 而肌瘤周围的假被膜纤维区 （5/6） 及假被膜血管壁 （2/6） 淀粉样沉积发生率高。（2） 2 组均可见炎性细胞浸润。（3） 淀粉样变沉积阳性及阴性部位均可见 PAS 阳性。（4） 2 组 HGB、 WBC、 NEU、 LYM、 TP、 Alb 和 PA 水平差异均无统计学意义 （P > 0.05）。结论 子宫肌瘤纤维细胞功能改变引起局部组织细胞代谢微环境的变化可能与淀粉样变形成有关。