SETDB1: A perspective into immune cell function and cancer immunotherapy

Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro-B to pre-B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL-2 and IL-17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD-L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy.     

Comparison between nafarelin acetate andd-Trp6-LHRH for temporary pituitary suppression in in vitro fertilization (IVF) patients: A prospective crossover study

Purpose Nafarelin acetate is a new gonadotropin releasing (GnRH) agonist analogue with unique potency, intranasal administration, and convenient storage. Hence, nafarelin was considered as an alternative for temporary pituitary suppression in patients undergoing ovulation induction in IVF. A crossover treatment in a prospective study was performed including 40 women with bilateral obstructed tubes and normal ovarian function, treated in 80 ovulation induction cycles using the long protocol. Twenty patients used nafarelin acetate 600 g/daily in their first cycle and received d-Trp6-LHRH, 0.5 mg/daily, in their following cycle. The other 20 women used decapeptyl in their first cycle and received nafarelin in the second.Results Estradiol suppression was achieved by both d-Trp6-LHRH and nafarelin at equal time intervals. The average total number of ampoules (P=0.0005) and the length of administration of hMG required for ovarian stimulation (P=0.0002) and the time interval between GnRHa initiation to oocyte retrieval (P=0.04) was significantly lower in nafarelin cycles. The number and the distribution between large and small follicles as well as the average number of oocytes retrieved did not differ between the two GnRH analogues.Conclusion Our results demonstrate that nafarelin acetate is comparable to d-Trp6-LHRH for temporary pituitary suppression used for controlled ovarian stimulation in IVF patients. However, using nafarelin ovarian stimulation was achieved with fewer ampoules of hMG, administered for a shorter period of time, thus with a lesser cost.     

MR脂肪抑制技术开发与临床应用

目的：通过ＭＲ脂肪抑制技术开发的结果,鉴别Ｔ_１加权像高信号病变。方法：利用荷兰ＰＨＩＬＩＰＳ０．５Ｔ磁共振机对３例对照组和６例病变组进行常规ＭＲ扫描和脂肪抑制（ＳＴＩＲ）扫描。结果：３例对照组的岩尖脂肪、枕项皮下脂肪。肾周脂肪常规扫描,Ｔ１Ｗ和Ｔ２Ｗ均为相似的高信号,脂肪抑制扫描无信号。病变组６例,即头部３例,颈椎及胸椎各１例,颈髓１例,常规扫描Ｔ_１Ｗ及Ｔ_２Ｗ均为高信号,脂肪抑制扫描则无信号。结论：Ｔ_１Ｗ为高信号时进行脂肪抑制扫描,脂肪受到抑制后出现特异性的无信号,可用来鉴别Ｔ_１Ｗ高信号病变。     

免疫状态对Fv—4基因抗Friend MuLV作用的影响

通过检测免疫抑制的Ｆ１小鼠和杂合子Ｆ２裸鼠对Ｆｒｉｅｎｄ小鼠白血病病毒（Ｆｒ．ＭｕＬＶ）感染的敏感性,探讨免疫状态对Ｆｖ－４基因（特别是对Ｆｖ－４基因杂合子）抗ＦｒｉｅｎｄＭｕＬＶ作用的影响,经腹腔接种Ｆｒ．ＭｕＬＶ病毒液攻击小鼠或Ｆ２裸鼠后,检查其计中Ｆｒ．ＭｕＬＶ的增主其发病情况,结果表明,免疫抑制的Ｆ１小鼠和杂合子Ｆ１裸鼠都可被Ｆｒ．ＭｕＬＶ脾脏中有病毒增殖,并用约２／３的杂合子Ｆ２裸鼠与Ｂ     

Effects of chlordiazepoxide,morphine and amphetamine on responding suppressed by different levels of electric shock in the pigeon are rate dependent

In general, chlordiazepoxide (CDP) and amphetamine reduce high rates of responding and increase low rates (rate-dependent effect). However, unlike CDP, amphetamine does not typically increase low rates resulting from suppression of responding by noxious stimuli. In the present experiment, key pecking by pigeons was reinforced under a random ratio schedule of food presentation. This responding was then suppressed by stimuli correlated with electric shocks of varying intensity (2 or 4 mA) or reduced by the omission of the food (extinction). Treatment with CDP (0.3–10.0 mg/kg) and morphine (0.3–10.0 mg/kg) increased the rate of suppressed responding: lower rates being increased to a proportionately greater extent than high rates.d-Amphetamine (0.1–1.0 mg/kg) further reduced the rate of suppressed responding: the lower rates being reduced proportionately more than the higher rates. Thus the effects of all three drugs depended upon the control rates of responding, but the effects of amphetamine were the inverse of those of CDP and morphine. The effects of amphetamine on low, suppressed or punished response rates are therefore not an exception to the generality of rate-dependency, but a different aspect of the same principle — inverse rate-dependency.     

Is a serotonergic mechanism involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the Sprague-Dawley rat?

The major cause of TCDD-induced death in rats is a progressive voluntary feed refusal which has been correlated with reduced gluconeogenesis. Since centrally administered TCDD does not cause death or decreased feed intake in rats, the ability of TCDD to suppress appetite via peripheral mechanisms acting on the central nervous system was examined in two experimental models. First, it was found that the feed intake of rats on scheduled feeding cycles was not decreased by blood transfused from rats with TCDD-induced appetite suppression (8 days after a lethal dose of TCDD, i.p.). In contrast, a similar transfusion from normal, satiated rats did reduce feed intake of recipient rats by approximately 40%, suggesting that TCDD-treated rats are not satiated but rather that they are not hungry. In the second study tryptophan (the amino acid precursor of the neurotransmitter serotonin) was measured in the plasma and tryptophan, serotonin, norepinephrine and dopamine in the hypothalamus as well as dopamine and its metabolites in the striatum 4, 8, and 16 days after TCDD dosage (125 g/kg, i.p.). Progressive time-dependent increases in tryptophan levels in plasma and brain were paralleled by increases in brain serotonin and 5-hydroxyindoleacetic acid (the primary metabolite of serotonin) in TCDD-treated rats. No changes were observed regarding the other biogenic amines. It is suggested based on these data and on substantial evidence from the published literature that a serotonergic mechanism may be involved in TCDD-induced feed intake reduction.     

Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors

CB1 cannabinoid receptors are widely distributed in the central nervous system where they mediate most of the cannabinoid-induced responses. Here we have evaluated the interactions between the CB1 cannabinoid receptors and the endogenous opioid system by assaying a number of well-characterized opioid responses, e.g. antinociception and stress-mediated effects, on mutant mice in which the CB1 receptor gene was invalidated. The spontaneous responses to various nociceptive stimuli (thermal, mechanical and visceral pain) were not changed in mutant CB1 mice. Furthermore, the absence of the CB1 cannabinoid receptor did not modify the antinociceptive effects induced by different opioid agonists: morphine (preferential mu opioid agonist), D-Pen2-D-Pen5-enkephalin (DPDPE) and deltorphin II (selective delta opioid agonists), and U-50,488H (selective kappa opioid agonist) in the hot-plate and tail-immersion tests. In contrast, the stress-induced opioid mediated responses were modified in CB1 mutants. Indeed, these mutants did not exhibit antinociception following a forced swim in water at 34 degrees C and presented a decrease in the immobility induced by the previous exposure to electric footshock. However, the antinociception induced by a forced swim in water at 10 degrees C was preserved in CB1 mutants. These results indicate that CB1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid-mediated responses to stress.     

离子抑制色谱法测定琥乙红霉素含量及其有关物质

目的　建立离子抑制色谱法测定琥乙红霉素原料的含量及有关物质的方法 ,并研究其影响因素。方法　采用ZorbaxSB -C1 8色谱柱 ,以 0 .0 2mol·L- 1 KH2 PO4 乙腈 ( 4 5∶5 5 ,用氨试液调至pH 6 .8)为流动相 ,流速 1.2mL·min- 1 ,检测波长 2 10nm ,柱温 ( 30± 0 .5 )℃。结果　在选定固定相条件下 ,流动相对组分的洗脱和选择性影响最大 ,柱温次之 ,琥乙红霉素在乙腈中比较稳定。测定了有效主成分琥乙红霉素A的含量以及 7个有关物质的总含量 ,琥乙红霉素A的平均回收率为 99.4 5 %(RSD =2 .2 4 % ,n =5 )。结论　本方法可用于琥乙红霉素原料的含量测定和有关物质的检查。     

人PTEN基因表达载体的构建及其在U251细胞中的表达

背景与目的:克隆人野生型和突变型PTEN的cDNA并构建其表达载体,探讨该表达质粒在人星形胶质瘤细胞U251中的表达情况.材料与方法:分别从新鲜胎盘组织和结肠癌组织中提取总RNA,采用RT-PCR的方法扩增人野生型和突变型PTEN基因全长cDNA,分别克隆入pMD 18-T载体上,经PCR、酶切鉴定均为阳性的克隆,进行核苷酸序列分析.再分别将两段基因定向克隆入pcDNA3.1( )载体中构建表达载体,转染入U251细胞.结果:成功克隆了人野生型及突变型PTEN cDNA并成功构建其表达载体,发现突变型PTEN蛋白对细胞生长无明显抑制作用,而野生型PTEN蛋白对细胞生长有明显抑制作用.结论:PTEN可能能抑制肿瘤细胞生长,为后进一步开展PTEN对肿瘤相关功能的研究奠定基础.     

人突变p27基因对大肠癌细胞SW480生长的影响

目的：观察人突变p27基因（p27mt）对人大肠癌细胞生长的影响，探讨p27mt基因在大肠癌基因治疗中的作用机制。方法：以携带突变p27基因复制缺陷型腺病毒（Ad—p27mt）为载体，转染大肠癌细胞SW480；用Western blot方法检测p27mt蛋白的表达；细胞计数法检测p27mt对SW480细胞生长的抑制作用；用流式细胞仪检测细胞周期：用DNA片段分析法检测细胞凋亡。结果：通过免疫印迹分析Ad—p27mt转染SW480细胞后，p27在细胞中出现了蛋白高表达。PI染色流式细胞仪检测77．96％的细胞阻滞于G0/G1期，而Ad—LacZ组及空白对照组分别为27．57％和25．29％；生长曲线显示Ad—p27mt对细胞生长就有明显的抑制作用；DNA片段分析示p27mt基因可诱导细胞的凋亡。结论：p27mt对细胞周期有明显的阻滞作用，主要阻滞于G0／G1期；p27mt基因对细胞的生长抑制机制与诱导细胞凋亡和细胞周期的阻滞有关。