Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specifc cell-permeable peptide inhibitor

Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identifcation of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efcacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.     

精神发育迟滞儿童的事件相关电位P300的特征

目的探讨精神发育迟滞（MR）儿童的事件相关电位P300的特征。方法对30名精神发育迟滞儿童（精神发育迟滞组）和30名正常儿童（正常对照组）分别进行事件相关电位P300测定，取P300的潜伏期和波幅，将所得结果进行统计学分析。结果与正常对照组相比，精神发育迟滞组儿童事件相关电位视觉P300波的潜伏期延长，波幅降低，差异显著（P〈0．05）。结论事件相关电位P300的潜伏期和波幅可客观地反映精神发育迟滞儿童的认知功能的变化，具有协助诊断的意义，可作为评价精神发育迟滞患儿的认知功能的客观指标之一。     

Melatonin down‐regulates MDM2 gene expression and enhances p53 acetylation in MCF‐7 cells

Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over‐expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome‐dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K‐AkT‐dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2‐dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down‐regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt‐PI3K‐dependent MDM2 phosphorylation. Melatonin induces a 3‐fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin‐treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15‐fold increase in p21 levels was observed in melatonin‐treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.     

Task relevance and recognition of concealed information have different influences on electrodermal activity and event‐related brain potentials

This study aimed at differentiating between memory‐ and task‐related processes and their correlates on the electrodermal and electrocortical level during information concealment. Variations of the Guilty Knowledge Test were implemented in two experiments while we measured skin conductance responses (SCRs) and event‐related brain potentials. P300 amplitudes were specifically enhanced for items requiring a deviant behavioral response but they were not sensitive to concealed knowledge. In contrast, N200 amplitudes differed between memorized and irrelevant items in both experiments. SCR measures reflected a combined influence of task relevance and probe recognition, and they provided incremental validity above N200 amplitudes. These results suggest that the P300 mainly reflects task relevance in the given experimental setting whereas the N200 amplitude is sensitive to previously encoded information and potentially linked to response monitoring processes.     

Frequency-domain analysis of fast oddball responses to visual stimuli: A feasibility study

Event-related potential responses to oddball stimuli, including the P300 component, have been proposed as a diagnostic tool for discerning psychiatric or higher-level neural disorders from malingering, for instance in cases of unexplained visual loss. For clinical use, short recording durations and easy statistical assessment are highly desirable. With this aim, we investigated the feasibility of recording oddball responses in a fast steady-state regime. We used gratings with two possible orientations in a rapid oddball paradigm with an inter-stimulus interval of 214 ms. Six consecutive presentations of one stimulus type (frequent) were followed by a single presentation of the other (infrequent) stimulus type. Subjects were attending to the rare stimulus type. The electroencephalographic recordings were analyzed in the frequency domain. All subjects produced significant harmonic responses related to the processing of the rare stimulus, demonstrating the feasibility of the technique, with the potential of reducing recording times substantially compared to conventional slow stimulation. We furthermore found that the regularity of the occurrence of infrequent stimuli, which is necessary for frequency-domain analysis, does not per se reduce the P300 responses, as would have been expected in the framework of some hypotheses regarding the role of the P300.     

miRNA-449a在肺癌组织中的表达及其检测意义

目的探讨miRNA-449a在肺癌组织中的表达及其临床应用价值。方法收集右江族医学院附属医院2011年1月1日~2013年6月30日收治的58例肺癌患者为研究对象,采用反转录荧光定量聚合酶链式反应(RT-PCR)检测miRNA-449a在肺癌组织和癌旁正常组织中的表达量,分析miRNA-449a与临床病理特征的关系,并采用荧光电子显微镜观察miRNA-449a模拟物对体外培养肺癌细胞株95D细胞凋亡的影响。结果鳞癌组和腺癌组miRNA-449a平均表达量均明显低于癌旁正常对照组(LSD-t=6.712,P=0.000;LSD-t=4.572,P=0.000),其相对表达量与瘤体大小(u=78.412,P=0.012)有关,与患者年龄(u=920.000,P=0.615)、性别(u=800.000,P=0.215)、病理类型(χ2=4.221,P=0.155)和临床分期(u=754.000,P=0.009)无关。与阴性对照组比较,miRNA-449a模拟物可明显促进肺癌细胞的凋亡,且呈剂量依赖性。结论 miRNA-449a在肺癌组织中呈低表达,可诱导肺癌细胞凋亡,发挥抑癌基因的作用,可能成为肺癌早期诊断与治疗的新分子靶标。     

慢性精神分裂症患者血清S100B水平与事件相关电位P300的相关性

目的:探讨慢性精神分裂症患者血清S100B水平与事件相关电位P300(Event-related potential P300,P300)的关系。方法:随机将年龄在18~60岁之间符合ICD-10及CCMD-3诊断标准的慢性精神分裂症患者40例作为研究组,选择40例健康者作为对照组。同时检测血清S100B水平及以P300评定认知功能,并将结果加以分析、比较。结果:与对照组相比,研究组CZ、PZ点的N1、P2、N2、P3潜伏期均明显延长(t=2.24~3.85,P0.05或0.01),研究组CZ、PZ点的N2、P3波幅明显降低(t=3.04~5.26,P0.01);研究组的血清S100B水平高于对照组(t=4.15,P0.01);CZ、PZ点P300潜伏期与血清S100B水平呈正相关(r=0.35~0.48,P0.05或0.01),CZ、PZ点P300波幅与血清S100B水平则呈负相关(r=-0.48~-0.58,P0.01)。结论:慢性精神分裂症患者血清S100B水平高于健康者并且认知功能存在损害,其认知功能损害可能与血清S100B水平有关。     

Long-latency auditory evoked potentials with verbal and nonverbal stimuli

IntroductionLong-latency auditory evoked potentials represent the cortical activity related to attention, memory, and auditory discrimination skills. Acoustic signal processing occurs differently between verbal and nonverbal stimuli, influencing the latency and amplitude patterns.ObjectiveTo describe the latencies of the cortical potentials P1, N1, P2, N2, and P3, as well as P3 amplitude, with different speech stimuli and tone bursts, and to classify them in the presence and absence of these data.MethodsA total of 30 subjects with normal hearing were assessed, aged 18–32 years old, matched by gender. Nonverbal stimuli were used (tone burst; 1000 Hz – frequent and 4000 Hz – rare); and verbal (/ba/ – frequent; /ga/, /da/, and /di/ – rare).ResultsConsidering the component N2 for tone burst, the lowest latency found was 217.45 ms for the BA/DI stimulus; the highest latency found was 256.5 ms. For the P3 component, the shortest latency with tone burst stimuli was 298.7 with BA/GA stimuli, the highest, was 340 ms. For the P3 amplitude, there was no statistically significant difference among the different stimuli. For latencies of components P1, N1, P2, N2, P3, there were no statistical differences among them, regardless of the stimuli used.ConclusionThere was a difference in the latency of potentials N2 and P3 among the stimuli employed but no difference was observed for the P3 amplitude.