In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Impact des facteurs psychosociaux sur la santé mentale du personnel de nettoyage

Purpose

To describe the relationship between psychosocial factors and mental health among housekeepers.

首发儿童精神分裂症患者脑源性神经营养因子水平及神经元凋亡研究

目的探讨首发儿童精神分裂症患者脑源性神经营养因子(BDNF)、β-微管蛋白III(Tuj-1)、胱天蛋白酶3(Caspase-3)的变化,为揭示儿童精神分裂症的病因和发病机制提供参考。方法以2015年8月-2018年3月在大理州第二人民医院就诊的符合《精神障碍诊断与统计手册(第4版)》(DSM-IV)诊断标准的儿童精神分裂症患者(n=35)为研究组,同期在大理州第二人民医院的体检儿童中随机选取健康儿童为对照组(n=30)。通过实时荧光定量逆转录-聚合酶链反应(RT-PCR)测定两组儿童血液中BDNF、Caspase-3和Tuj-1的mRNA表达水平。结果与对照组相比,研究组BDNF和Tuj-1 mRNA表达低(P0.05或0.01),Caspase-3 mRNA表达高(P0.01)。结论儿童精神分裂症患者的BDNF mRNA和Tuj-1 mRNA表达少,Caspase-3 mRNA表达多,BDNF mRNA、Tuj-1 mRNA和Caspase-3 mRNA可能与儿童精神分裂症相关。     

形觉剥夺性高度近视豚鼠巩膜形态改变及缺氧诱导因子-1α和氧自由基在高度近视中的作用

目的　观察形觉剥夺性高度近视（form deprivation high myopia，FDHM）豚鼠巩膜形态变化，探讨缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）及氧自由基在高度近视中的作用。方法　将豚鼠适应性饲养1周后，随机分为空白对照组（25只）和模型组（25只）。模型组豚鼠右眼行眼睑缝合，所有模型组豚鼠均选择右眼作为FDHM组，对侧眼为自身对照组。空白对照组豚鼠不做任何处理。于造模前及造模后8周采用检影镜测量屈光度，A超进行生物测量。形觉剥夺8周以后处死豚鼠，观察巩膜形态和超微结构的变化，测定巩膜HIF-1α相对表达量，超氧化物歧化酶（superoxide dismutase，SOD）活力及丙二醛（malondialdehyde，MDA）的含量。结果　豚鼠形觉剥夺8周以后，FDHM组屈光度从（+3.59±0.33）D变为（-7.96±0.55）D，明显高于空白对照组（+0.89±0.32）D、自身对照组（-0.55±0.49）D（均为P<0.05）；玻璃体腔深度为（4.12±0.13）mm明显高于空白对照组（3.71±0.23）mm和自身对照组（3.93±0.04）mm（均为P<0.05）；眼轴长度为（8.93±0.22）mm明显长于空白对照组（7.95±0.37）mm和自身对照组（8.01±0.15）mm（均为P<0.05）。巩膜组织明显变薄，细胞外基质增多，成纤维细胞密度降低，胶原纤维平均直径减小。FDHM组巩膜中HIF-1α相对表达量、MDA含量明显高于空白对照组和自身对照组，SOD活力明显低于空白对照组和自身对照组（均为P<0.05）。结论　形觉剥夺8周后，豚鼠FDHM眼近视度数明显增加，玻璃体腔深度增加，眼轴延长，巩膜形态发生病理性变化；HIF-1α、SOD、MDA可能参与了FDHM的形成。     

Responses of Types 1 and 2 Neovascularization in Age-Related Macular Degeneration to Anti-Vascular Endothelial Growth Factor Treatment: Optical Coherence Tomography Angiography Analysis

Purpose: To compare the responses of types 1 (sub-pigment epithelial) and 2 (subretinal) neovascularization in neovascular age-related macular degeneration (AMD) to anti-vascular endothelial growth factor (VEGF) treatment.

Methods: Fifty-five treatment-naïve neovascular AMD eyes (53 patients) were retrospectively included for analysis. All patients were treated with three loading injections of anti-VEGF agent, followed by further injections as required. The lesion size and vascular density of type 1 and 2 lesions before and after treatment for 12 months were analyzed using optical coherence tomography angiography (OCTA).

Results: The mean lesion size of the type 1 neovascularization group (42 eyes) showed no significant change from 2.12 ± 1.01 mm² at baseline to 2.08 ± 0.91 mm² at 12 months (P = .682). However, the mean lesion size of type 2 neovascularization significantly decreased from 1.23 ± 0.93 mm² at baseline to 0.79 ± 0.61 mm² at 12 months (P = .022). The proportion of eyes with lesion sizes that decreased by more than 40% from baseline was also significantly higher for the type 2 compared to the type 1 neovascularization group (46.2% versus 11.9%, P = .007). Vascular density showed no significant changes for both groups after treatment and showed no association with the change in lesion size. There was no significant difference between the groups in terms of visual acuity improvement.

Conclusion: OCTA analysis revealed different responses to anti-VEGF treatment depending on the location of neovascularization in neovascular AMD. Type 2 neovascularization was significantly regressed compared to type 1 neovascularization after anti-VEGF treatment. However, the changes in vascular density and visual outcome showed no significant differences between groups after 12 months of treatment.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.