免疫检查点抑制剂在转移性结直肠癌患者治疗中的研究进展

免疫检查点抑制剂的出现,增加了许多实体肿瘤的治疗选择。尽管在黑素瘤和肺癌的治疗中效果良好,但大多数转移性结直肠癌患者无法从免疫治疗中获益。免疫检查点抑制剂在错配修复功能缺失转移性结直肠癌患者中明确有显著和持久的临床反应,即使在既往多线治疗失败的群体中也是如此。然而,这种临床获益仅限于小部分肿瘤患者,约占转移性结直肠癌的4%。事实上抗程序性死亡受体1(programmed cell death protein 1,PD-1)单抗对错配修复功能缺失转移性结直肠癌患者是无效的。迫切需要新颖的治疗策略使这些肿瘤具有免疫应答。破坏肿瘤的疗法(化学疗法,放射疗法和靶向疗法),从而释放肿瘤抗原,是免疫检查点抑制和其他疗法相结合的最直接的策略。这些标准疗法远没有像曾经担心的那样削弱免疫反应,反而还可以增强免疫应答。     

表没食子儿茶素没食子酸酯对人成淋巴细胞株hMLH1 和hMSH2 mRNA表达的影响

目的： 探讨表没食子儿茶素没食子酸酯[(-)epigallocatechin gallate ，EGCG]对人成淋巴细胞株错配修复基因hMLH1和hMSH2 mRNA表达水平的影响。方法：将正常人成淋巴细胞株GM12593和乳腺癌患者成淋巴细胞株GM13705分别置于含有0、5、10、20 μmol/L EGCG的RPMI-1640中进行6 d干预培养后，采用实时荧光定量PCR (FQ-PCR)技术检测干预前后错配修复基因hMLH1和hMSH2 mRNA表达水平的变化。结果：经20 μmol/L EGCG干预培养6 d后，GM12593细胞hMLH1与hMSH2 mRNA表达水平均显著高于其他浓度组 (P均<0.05)，且显著高于同等浓度时GM13705细胞中上述2个基因的表达水平(P<0.05)；EGCG对GM13705 目标基因的表达无显著影响 (P>0.05)。结论：EGCG具有上调正常人成淋巴细胞株hMLH1与hMSH2 mRNA表达水平的潜力，可能通过增加错配修复起始复合物的数量，来帮助错配修复机制的启动，维护基因组的稳定性。     

Electrophysiologic and Neuropsychologic Evaluation of Patients with Centrotemporal Spikes

The present study was designed to evaluate neurocognitive functions with endogenous potentials and neurophysiologic tests in patients with centrotemporal spikes who were not on any medication. Of the patients, 85.7% had seizures, 9.5% had pavor nocturnes, and 4.8% had atypical headache. The patients, especially who had atypical seizures or left-sided epileptic activity, were found to have significant visuomotor function impairment (p <.05). In P300 test, N2P3 amplitude was lower in the patients, particularly who had left sided epileptic activity (p <.05). MMN and LDN results were normal. Serial evaluations of such patients with endogenous potentials and neuropsychological tests may be helpful to show development of neurocognitive impairment.     

Increased perseverative errors following high-definition transcranial direct current stimulation over the ventrolateral cortex during probabilistic reversal learning

BackgroundThe prefrontal cortex regulates behavioural adaptation in response to feedback. However, the causal role of different prefrontal regions remains unclear, based on indirect evidence derived from functional neuroimaging. Neuroimaging studies show dorsomedial prefrontal activation during feedback monitoring, whereas the ventrolateral prefrontal cortex engages during behavioural adaptation (shifting).ObjectiveWe used high-definition transcranial direct current stimulation (HD-tDCS) to elucidate the roles of the ventrolateral prefrontal cortex (vlPFC) and the dorsomedial prefrontal cortex (dmPFC) in behaviour change, using a probabilistic reversal learning task (PRLT).MethodFifty-two healthy adults were randomly assigned to receive cathodal HD-tDCS to inhibit the vlPFC or the dmPFC versus sham stimulation, prior to completing the PRLT. The outcome measures were the number of perseverative errors and the electroencephalography (EEG) signals of feedback-related negativity (FRN) in the PRLT. We hypothesised that inhibition of the vlPFC would be specifically associated with more perseverative errors and weaker FRNs.ResultsWe found that vlPFC inhibition was associated with higher perseverative errors compared to sham and dmPFC stimulation conditions. Although there were no statistically significant differences in FRN amplitudes, the effect sizes indicate an association between inhibition of the vlPFC and lower FRN amplitudes.ConclusionOur findings support a causal role of the vlPFC on feedback-based behavioural adaptation, which is critical for adaptive goal-driven behaviour.     

Mismatch repair system in endometriotic tissue and eutopic endometrium of unaffected women

Objective: To test the immunohistochemical staining pattern of some mismatch repair (MMR) system proteins in endometriotic tissue (ET) and eutopic endometrium. Methods: This was a retrospective study conducted at the Pathology and Obstetrics and Gynecology Departments of the Udine University Hospital. We analyzed 528 samples obtained from 246 patients affected by endometriosis and 71 samples from 71 patients with normal endometrium. A tissue microarray model was used to analyze the immunohistochemical expression of MMR system proteins. Results: Significant loss of MMR proteins was found in the stromal component of ETs. We found MSH2 to be expressed at a higher level than any other MMR system proteins in eutopic endometrium and ETs, to be significantly correlated to Ki-67 expression in both stromal and glandular components of ETs, and to be expressed at a significantly higher level in ETs than in eutopic endometrium. When considering the subgroup of endometriosis with high recurrence rate and glandular cytoplasmic staining for aurora A kinase, we found MMR proteins expressed at a significantly higher level in these ETs than in other ETs and eutopic endometrium of unaffected women. Conclusions: We found significant loss of MMR proteins (known to be associated with microsatellite instability) in the stromal component of ETs. The group of ETs with glandular cytoplasmic staining for aurora A kinase had higher MMR protein expression, suggesting an increased activity of this system. Our result suggests a novel role of increased MSH2 expression in cellular proliferation of endometriosis.     

God will forgive: reflecting on God’s love decreases neurophysiological responses to errors

In religions where God is portrayed as both loving and wrathful, religious beliefs may be a source of fear as well as comfort. Here, we consider if God’s love may be more effective, relative to God’s wrath, for soothing distress, but less effective for helping control behavior. Specifically, we assess whether contemplating God’s love reduces our ability to detect and emotionally react to conflict between one’s behavior and overarching religious standards. We do so within a neurophysiological framework, by observing the effects of exposure to concepts of God’s love vs punishment on the error-related negativity (ERN)—a neural signal originating in the anterior cingulate cortex that is associated with performance monitoring and affective responses to errors. Participants included 123 students at Brigham Young University, who completed a Go/No-Go task where they made ‘religious’ errors (i.e. ostensibly exhibited pro-alcohol tendencies). Reflecting on God’s love caused dampened ERNs and worse performance on the Go/No-Go task. Thinking about God’s punishment did not affect performance or ERNs. Results suggest that one possible reason religiosity is generally linked to positive well-being may be because of a decreased affective response to errors that occurs when God’s love is prominent in the minds of believers.