依维莫司联合全反式维甲酸逆转急性早幼粒细胞白血病细胞耐药的研究

目的探讨依维莫司联合全反式维甲酸(简称维甲酸)逆转急性早幼粒细胞白血病(APL)细胞株NB4-R1耐药的作用。方法应用CD11b染色流式细胞术及硝基四唑氮蓝(NBT)还原实验检测两药联合应用对细胞分化的影响, 流式细胞术检测细胞周期情况, Annexin V/PI双染色检测细胞凋亡情况, 蛋白质印迹法检测自噬相关蛋白微管结合蛋白轻链3(LC3)、Beclin 1及早幼粒白血病-维甲酸受体融合蛋白(PML-RARα)、磷酸化核糖体S6激酶(P-P70S6K)、磷酸化4E结合蛋白1(P-4E-BP1) 等表达水平。结果与维甲酸组比较, 联用组能诱导耐药细胞株NB4-R1细胞的分化, 并将细胞增殖阻止在G ₁期而对细胞凋亡无明显影响。100 nmol/L依维莫司组、1μmol/L维甲酸组、联用组、对照组NB4-R1细胞培养48 h后分化百分率分别为(2.29±0.57)%、(17.06±2.65)%、(54.47±4.91)%、(2.54±0.53)%; 处于G ₁期的细胞百分率分别为(35.20±11.97)%、(33.54±6.25)%、(53.70±8.73)%、(27.40±6.01)%; 四组细胞凋亡细胞百分率分别为(2.30±0.14)%、(2.25±0.21)%、(2.40±0.28)%、(1.95±0.07)%。与维甲酸组比较, 联用组mTOR信号通路下游的P70S6K、4E-BP1分子磷酸化水平下降, LC3-II和Beclin 1的表达上调, 且能部分降解融合蛋白PML-RARα。 结论依维莫司联合维甲酸能诱导NB4-R1细胞分化, 且能阻滞细胞周期而不致细胞凋亡, 其机制可能与依维莫司联合维甲酸抑制mTOR信号通路激活自噬作用从而降解PML-RARα蛋白有关。     

The relationships among monocyte subsets,miRNAs and inflammatory cytokines in patients with acute myocardial infarction

Background

Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF-α and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI.

Advances in Causal Chain Development and Testing in Alcohol Research: Mediation, Suppression, Moderation, Mediated Moderation, and Moderated Mediation

Background:  While causal modeling is generally well known to alcohol researchers, several causal structures (including suppression, mediated moderation, and moderated mediation) are often poorly understood and seldom employed when investigators seek to model the complex mechanisms of behavior change, despite their widespread applicability to the field.
Methods:  This paper compares and contrasts five basic structures of causal modeling in the context of contemporary alcohol research and demonstrates how mechanisms of behavior change can be conceptualized and tested as parallel and serial sequences of these basic causal structures, forming causal chains.
Conclusion:  Recent methodological developments, while representing an important advancement for the field, fail to adequately address the complexities of alcohol dependence phenomena. A differentiation between frequently combined forms of these causal structures is proposed that would better address the needs of the field.     

大肠黏膜癌变过程中PTEN和p27的表达及相关性研究

目的 :探讨PTEN及p2 7在大肠黏膜癌变过程中的表达及两者的相关性。方法 :采用免疫组织化学S -P法检测了 5 8例大肠癌 ,15例腺瘤性息肉及 11例配对的癌旁正常组织中抑癌基因PTEN和 p2 7的蛋白表达。分析PTEN和 p2 7的表达情况及与各种临床病理特征的关系及两者的相关性。结果 :在癌旁正常组织、大肠腺瘤性息肉、大肠癌组织中PTEN表达率分别为 (97.3± 4 .3) % ,(85 .2± 16 .8) % ,(13.8± 17.6 ) % ,呈递减趋势。大肠癌DukesA/B期组PTEN蛋白的高表达率为 88.9% ,明显高于DukesC/D期组中的 5 1.6 %。PTEN的高表达率与性别、年龄、肿瘤的大小、部位、分化程度、有无淋巴结转移无关。p2 7主要表达在细胞核 ,也有少量表达在细胞浆。在癌旁正常组织、大肠腺瘤性息肉、大肠癌组织中p2 7高表达率分别为 (98.8± 1.0 8) % ,(86 .0± 13.6 ) % ,(5 6 .8± 2 6 .0 ) % ,呈递减趋势。在大肠癌高、中分化组中 p2 7蛋白的表达率为 71.4 % ,明显高于低分化组中的 2 3.1%。p2 7的高表达率与患者的Dukes分期、性别、年龄、肿瘤的大小、部位及有无淋巴结转移无关。在大肠癌组织中 ,PTEN与 p2 7蛋白的表达呈正相关 (r =0 .6 4 2 )。结论 :PTEN及p2 7表达在癌旁正常组织、大肠腺瘤性息肉、大肠癌组织中均呈递减趋势 ,提示P     

328. Mechanismen der langzeitakzeptanz allogener rattenlebertransplantate: makrophagenaustausch und suppressorzellaktivierung

Summary After orthotopic rat liver transplantation in the fully allogeneic BN (RT-1n) to LEW (RT-11) combination, the phenomenon of spontaneous tolerance of donor antigen occurs. We demonstrate two different immune mechanisms that may account for this process. Using adoptive transfer assays we show the presence of donor-specific T-suppressor lymphocytes in the spleens of long-term surviving liver graft, recipients. These cells prolong - adoptively transferred into irradiated syngeneic hosts — the survival of donor-specific (BN) but not third-party (DA) renal allografts (I00 days vs 1I days in control groups). Secondly, we demonstrate the replacement of Kupffer cells in the graft by recipient macrophages using polymorphic monoclonal antibodies in an immunoperoxidase technique. This may contribute to graft adaptation and thus to long-term graft acceptance.     

Effects of Carbamazepine on Murine Humoral and Cellular Immune Responses

Summary: Oral administration of carbamazepine (CBZ)(15, 10, or 5 mg/kg) to mice significantly decreased both humoral and cellular immune responses evaluated by enumeration of direct and indirect plaque-forming spleen cells (PFC) and delayed–type hypersensitivity reaction (DTH) against sheep red blood cells (SRBC) as compared with those observed in normal control animals. Moreover, spleen T cells obtained from CBZ–treated donor mice were capable of decreasing both PFC and DTH responses of normal spleen cells transferred into lethally irradiated recipient animals. The immunodepressor effect of CBZ was observed even though administration of CBZ induced augmentation of spleen cellularity.     

Immunologische Toleranz nach experimenteller Lebertransplantation

Zusammenfassung Im Vergleich zu anderen primär vaskularisieren Organtransplantaten in der Ratte werden Lebertransplantate schwächer abgestoßen, besitzen eine bessere Überlebensrate und können in bestimmten Spender-Empfänger-Kombinationen eine spenderspezifische Hyporeaktivität oder Toleranz induzieren. In dieser Übersicht werden die immunologischen Mechanismen dieses privilegierten Status beleuchtet. Eine Vielzahl möglicher Mechanismen, wie die Generation von Suppressor-T-Zellen, humorale Faktoren und Mikrochimärismus, sind mit der beobachteten Hyporeaktivität in Verbindung gebracht worden. Eine weitere Analyse dieser Phänomene könnte zur Entwicklung von Protokollen für die klinische Organ-transplantation beitragen, die zur Etablierung einer spenderspezifischen Hyporeaktivität ohne die Notwendigkeit einer lebenslangen Immunsuppression führen.

---

Immunologic tolerance following liver transplantation

Allografts in the rat liver are rejected less vigorously than other primarily vascularized allografts; they show a better survival rate and induce donor-specific unresponsiveness or tolerance in some donor-recipient combinations. This overview focuses on the immunologic mechanisms of this privileged status of liver allografts. A variety of possible mechanisms, such as generation of suppressor T-cells, humoral factors and microchimerism, has been related to the observed hyporeactivity. A further analysis of these phenomena may enhance the development of clinical organ transplantation protocols that allow for establishment of donor-specific unresponsiveness without the need for life-long immunosuppression.

     

Turnip crinkle virus coat protein mediates suppression of RNA silencing in Nicotiana benthamiana

All of the protein products of Turnip crinkle virus (TCV; Tombusviridae, Carmovirus) were tested for their ability to suppress RNA silencing of a reporter gene after transient expression in Agrobacterium-infiltrated Nicotiana benthamiana leaves. Only the capsid protein, P38, showed suppression activity, although this was not obvious when P38 was expressed as part of a TCV infection of the same tissues. When P38 was expressed from a PVX vector, symptoms with enhanced severity that correlated with increased PVX RNA accumulation were observed. This contradiction between ectopic expression of P38 and TCV infection could be accounted for if the active determinant of suppressor activity within P38 was sequestered within the capsid protein structure. The N-terminal 25 amino acids were shown to be important for this activity. This region forms part of the unexposed R-domain that interacts with the RNA within the virus particle. This observation throws light on some of the complex biology exhibited by TCV.     

Histamine activates suppressor cellsin vitro using a coculture technique

Aliquots of human blood mononuclear cells were culturedin vitro in the absence or presence of varying concentrations of histamine (10^–3–10^–8 M) for 24 hr, mitomycin treated, washed, and cocultured with autologous indicator cells that were then stimulated by PHA. The degree of suppression of thymidine uptake was measured in the presence of histamine-activated cells. The results demonstrated that histamine, in a dose-dependent fashion (10^–3 and 10^–4 M), significantly suppressed the PHA proliferative response. A minimum of 2 hr was required to activate cells by histamine to express suppressor function. While initial studies were carried out with a 1:1 suppressor:indicator cell ratio, it was found that maximum suppression resulted with lower rations (1:2 or 1:5) in some experiments, and was dependent somewhat on the concentration of histamine used. That the suppressor cells expressed histamine receptors was shown by the finding that histamine-Sepharose columns (but not control columns) depleted the histamine-reactive cells. In addition, Con A-reactive suppressor cells also adhered to histamine columns. Based on experiments with H₁ and H₂ antagonists and agonists, the histamine-responsive cell was apparently activated through its histamine type-2 receptor.     

EB病毒和ConA诱导抑制性T细胞对EB病毒感染B细胞作用探讨

本文探讨了用灭活的EB病毒(EBV)和ConA诱导产生的抑制性T细胞(Ts),对EBV感染自身B细胞的影响,结果表明,EBV抗原诱导产生的抑制性T细胞(Ts)能使EBV感染B细胞中的EBNA阳性细胞数,~3H-TdR掺入量和IgA、IgG及IgM分泌量减少;而ConA诱导产生的Ts则使EBNA阳性细胞数和~3H-TdR掺入量增加,但三种Ig含量无明显变化(P>0.05)。结果提示前者对EBV感染B细胞的激活,增殖和分化均有明显抑制作用,而后者的作用则相反,具有明显促进EBV感染B细胞的作用。