低氧性肺动脉高压发病中钾通道及促细胞生长因子的作用及防治研究

我们通过研究钾通道、碱性成纤维细胞生长因子(bFGF)和血管内皮细胞生长因子(VEGF)在低氧性肺动脉高压(HPH)发病过程中的变化,以及钾通道开放剂克罗卡啉(cromakalim)和左旋克罗卡啉(levocromakalim)、VEGF抑制剂干扰素诱导蛋白-10(IP-10)、bFGF抑制剂苏拉明以及汉防己甲素肺靶向微球对HPH的防治作用,探讨钾通道和细胞生长因子在HPH发病中的作用以及防治措施。     

P300 and positive slow waves reveal the plausibility in inductive reasoning

Category‐based induction is an advanced cognitive function that is based on our category‐level knowledge. Previous findings have recognized the distance effect in category‐based induction: Inductive strength is affected by the hierarchical distance between the premises and conclusions. However, the neural mechanisms underlying this effect require elucidation. In the present study, we investigated the neural mechanisms of the distance effect by using EEG technology and a new experimental paradigm—category‐based induction. In this paradigm, we used three hierarchical levels of categories—the subordinate category, the basic category, the superordinate category—and an irrelevant category. We further used these categories to create four types of trial that varied in the hierarchical distance between the premise and the conclusion: the subordinate‐basic, the basic‐superordinate, the subordinate‐superordinate, and the irrelevant‐superordinate trials. In each trial, participants judged the probability that the conclusion category had the same property as the premise category. Our behavioral results revealed that people responded more slowly in the irrelevant‐superordinate trials than in the basic‐superordinate and the subordinate‐basic trials. Our ERP results showed that the irrelevant‐superordinate trials elicited smaller P300 (250–500 ms) amplitudes than did the subordinate‐basic and the basic‐superordinate trials. In addition, the subordinate‐superordinate trials elicited smaller P300 and PSW (700–998 ms) amplitudes than did the subordinate‐basic and the basic‐superordinate combinations. These findings indicate that the amplitudes of P300 and PSW may reflect the distance effect in inductive reasoning: The further the premise‐conclusion hierarchical distance, the lower the inductive strength, and thus the smaller the P300 and PSW amplitudes.     

Prognostic significance of resident CD103+CD8+T cells in human colorectal cancer tissues

The prognostic significance and clinical implications of resident CD103⁺CD8⁺T cells in human colorectal cancer tissues still remains largely unexplored. In our present study, we aimed to characterize the resident CD8⁺T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance of resident CD8⁺T cells in colorectal cancer. We found that the OS rate of the colorectal cancer patients with higher infiltration of CD8⁺T cells, or with higher numbers of resident CD103⁺CD8⁺T cells, or with higher ratio of CD103⁺CD8⁺T cells over total CD8⁺T cells in cancer tissues was significantly better than that of the patients with lower infiltration of CD8⁺T cells, or with lower numbers of resident CD103⁺CD8⁺T cells, or with higher ratio of CD103⁺CD8⁺T cells over total CD8⁺T cells in cancer tissues, respectively. Moreover, higher infiltration of CD8⁺T cells in colorectal cancer tissues was significantly and inversely correlated with advanced TNM stage. Higher numbers of resident CD103⁺CD8⁺T cells in colorectal cancer tissues were significantly and inversely correlated with distant metastasis status. Higher ratio of CD103⁺CD8⁺T cells over total CD8⁺T cells in colorectal cancer tissues was significantly and inversely correlated with age status. The COX model analysis demonstrated that higher infiltration of CD8⁺T cells, higher numbers of resident CD103⁺CD8⁺T cells, or higher ratio of CD103⁺CD8⁺T cells over total CD8⁺T cells in colorectal cancer tissues, could serve as independent prognostic predictors for colorectal cancer patients. Taken together, our present study demonstrated the density of tumor infiltrating CD8⁺T cells or the numbers of resident CD103⁺CD8⁺T cells in colorectal tissues could be used as an important prognostic predictor for this malignancy.     

YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance by suppressing caspase-mediated apoptosis

The objective of this study was to characterize the oncogenic actions of a recently identified cancer-associated gene YWHAZ (also named as 14-3-3 ζ/δ) in urothelial carcinomas of the urinary bladder (UCUB). A genome-wide study revealed YWHAZ to be involved in the amplicon at 8q22.3, and its genetic amplification was detected predominantly in muscle-invasive bladder cancer (MIBC). Immunohistochemical staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis and STRING network studies suggested involvement of YWHAZ in regulating caspase-mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low endogenous YWHAZ levels boosted cell resistance to doxorubicin and cisplatin, as well as to ionizing radiation. Conversely, YWHAZ-knockdown using specific shRNA in cells with high endogenous YWHAZ levels diminished survival activity, suppressing cell growth and increasing cell death. Our findings confirm the essential role played by YWHAZ in sustaining cell proliferation during chemo/radiotherapy. Treatments based on anti-YWHAZ strategies may thus be beneficial for UCUB patients overexpressing YWHAZ. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN-deficient primary human glioblastoma

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP-ribosylation factor like-4C (ARL4C) was highly expressed in PTEN-deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway-mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull-down assay identified that ARL4C accelerated tumor progression via RAC1-mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease-free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN-deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.