Discovery of structure-based small molecular inhibitor of αB-crystallin against basal-like/triple-negative breast cancer development in vitro and in vivo

αB-crystallin (CRYAB) is present at a high frequency in poor prognosis basal-like breast tumours, which are largely absent of oestrogen, progesterone receptors and HER2 known as triple-negative breast cancer (TNBC). CRYAB functions as a molecular chaperone to bind to and correct intracellular misfolded/unfolded proteins such as vascular endothelial growth factor (VEGF), preventing non-specific protein aggregations under the influence of the tumour microenvironment stress and/or anti-cancer treatments including bevacizumab therapy. Directly targeting CRYAB can sensitize tumour cells to chemotherapeutic agents and decrease tumour aggressiveness. However, growing evidence shows that CRYAB is a critical adaptive response element after ischemic heart disease and stroke, implying that directly targeting CRYAB might cause serious unwanted side effects. Here, we used structure-based molecular docking of CRYAB and identified a potent small molecular inhibitor, NCI-41356, which can strongly block the interaction between CRYAB and VEGF₁₆₅ without affecting CRYAB levels. The disruption of the interaction between CRYAB and VEGF₁₆₅ elicits in vitro anti-tumour cell proliferation and invasive effects through the down-regulation of VEGF signalling in the breast cancer cells. The observed in vitro anti-tumour angiogenesis of endothelial cells might be attributed to the down-regulation of paracrine VEGF signalling in the breast cancer cells after treatment with NCI-41356. Intraperitoneal injection of NCI-41356 greatly inhibits the tumour growth and vasculature development in in vivo human breast cancer xenograft models. Our findings provide ‘proof-of-concept’ for the development of highly specific structure-based alternative targeted therapy for the prevention and/or treatment of TNBC.     

Effects of miR-200a and FH535 combined with taxol on proliferation and invasion of gastric cancer

Gastric cancer is one of the most common cancers in the world; taxol displayed modest efficacy as first-line chemotherapy for gastric cancer, conversely, it has limitations used alone. β-catenin is a multifunctional oncogenic protein and the elevation in expression and activity of β-catenin has been implicated in many cancers. Therefore, we assume that the inhibition of β-catenin can enhanced the efficacy of taxol. The purpose of this study was to investigate the inhibitory effect of miR-200a mimics, FH535 combined with taxol on proliferation and invasion of human gastric cancer cell lines SGC-7901 and BGC-823. In the current study, we identified that the combination of FH535 and miR-200a with taxol had potent growth-inhibitory and pro-apoptotic effects. Further, similar results were also observed in vivo, intratumoral injection of FH535, taxol and miR-200a mimics which also delayed tumor growth in nude mice harboring subcutaneous SGC-7901 xenografts. Collectively, miR-200a and FH535 can enhance the inhibitory effect of taxol on cell proliferation and moderate the invasion of human gastric cancer.     

Diagnosis and treatment of vertebral hemangiomas with neurologic deficit: a report of 29 cases and literature review

Background contextVertebral hemangiomas (VHs) are called benign tumors but are actually just vascular malformations. The diagnosis and treatment for aggressive VHs is still controversial, due to their rarity.PurposeTo evaluate the safety and efficiency of the present diagnostic methods and treatment choices.Study designA retrospective study of aggressive VHs with neurologic deficit.Patients sampleA total of 29 consecutive aggressive VH cases were diagnosed and treated in our department since 2001.Outcome measuresWe routinely took anteroposterior and lateral spinal roentgenograms, computed tomography, and magnetic resonance images.MethodsTrocar biopsy is indicated in suspected malignant cases. Radiotherapy was usually our first choice if the neurologic deficit was mild or developed slowly. Surgery was indicated if the neurologic deficit was severe or developed quickly or if the radiotherapy was not effective.ResultsThis series included 12 males and 17 females, and the mean age at diagnosis was 44.0 years (range, 21–72 years). Ten patients had radiculopathy, 1 had cauda equina syndrome, and 18 cases had myelopathy. Twenty-one cases had lesions in the thoracic spine, 5 in the lumbar, and 3 in the cervical region. Eleven cases had untypical image findings, including five cases with pathologic vertebral fracture. The neurologic compression came from only epidural soft tumor mass in 18 cases, whereas it came from both bony compression and soft lesion in the other 11 cases. Ten cases had radiotherapy alone, but two failed and had surgery later. Twenty-one cases had surgery. In the 12 cases having surgical decompression without vertebroplasty, the average estimated blood loss was 1900 mL, and it was 1093 mL for the eight cases having decompression with vertebroplasty. The average follow-up was 51.1 months (range, 24–133 months). There was no recurrence in those cases with radiotherapy, whereas three had local recurrence in those six cases treated by surgical decompression alone without radiotherapy.ConclusionsIn aggressive VHs, epidural soft-tissue compression was usually the main reason for neurologic deficit. In cases with rapid progressive and/or severe myelopathy, posterior decompression and stabilization could be combined with intraoperative vertebroplasty to reduce blood loss.     

Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression

Mitochondrial dysfunction leads to reactive oxygen species (ROS) overload, exacerbating injury in myocardial infarction (MI). As a receptor for translocases in the outer mitochondrial membrane (Tom) complex, Tom70 has an unknown function in MI, including melatonin‐induced protection against MI injury. We delivered specific small interfering RNAs against Tom70 or lentivirus vectors carrying Tom70a sequences into the left ventricles of mice or to cultured neonatal murine ventricular myocytes (NMVMs). At 48 h post‐transfection, the left anterior descending coronary arteries of mice were permanently ligated, while the NMVMs underwent continuous hypoxia. At 24 h after ischemia/hypoxia, oxidative stress was assessed by dihydroethidium and lucigenin‐enhanced luminescence, mitochondrial damage by transmission electron microscopy and ATP content, and cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick‐end labeling and caspase‐3 assay. At 4 weeks after ischemia, cardiac function and fibrosis were evaluated in mice by echocardiography and Masson's trichrome staining, respectively. Ischemic/hypoxic insult reduced Tom70 expression in cardiomyocytes. Tom70 downregulation aggravated post‐MI injury, with increased mitochondrial fragmentation and ROS overload. In contrast, Tom70 upregulation alleviated post‐MI injury, with improved mitochondrial integrity and decreased ROS production. PGC‐1α/Tom70 expression in ischemic myocardium was increased with melatonin alone, but not when combined with luzindole. Melatonin attenuated post‐MI injury in control but not in Tom70‐deficient mice. N‐acetylcysteine (NAC) reversed the adverse effects of Tom70 deficiency in mitochondria and cardiomyocytes, but at a much higher concentration than melatonin. Our findings showed that Tom70 is essential for melatonin‐induced protection against post‐MI injury, by breaking the cycle of mitochondrial impairment and ROS generation.     

适合机械性取栓的急性栓塞性脑梗死动物模型的建立与评价

目的:建立并评价适合动脉内机械取栓的急性栓塞性脑梗死动物模型。方法:血流临时阻断凝血酶注入法制作急性栓塞性脑梗死模型,利用颅内动脉取栓装置行机械性取栓。应用数字减影血管造影(DSA)、磁共振弥散成像(DWI)、经颅多普勒及病理检查来评价模型建立的效果,比较模型建立前后表观弥散系数(ADC)、大脑中动脉流速(Vmca)变化情况。结果:DSA显示制模的成功率为83%。栓塞6 h DWI显示梗塞灶,24 h病理检查TTC染色可见梗死区。取栓后颈总动脉再通率为80%,栓塞前后、取栓前后Vmca的比较差异有统计学意义(P<0.05),取栓组与非治疗组6 h Vmca比较差异有统计学意义;取栓组ADC值呈上升趋势,非治疗组ADC值下降,两组24 h的比较差异有统计学意义(P<0.05)。结论:本研究所建立的模型稳定,重复性好,适用于颅内动脉取栓装置的实验研究和疗效评价。     

T-bet与Thl/Th2在乙型肝炎中的作用机制

T-bet是T-box家族的一种重要转录因子,在CD4+T细胞Thl型的分化中起重要作用,并抑制Th2细胞因子合成,可使完全分化的Th2逆转为Th1。目前已证实多种疾病的发生、发展和预后涉及Thl/Th2分化失衡。而T-bet对Thl/Th2分化调控作用在疾病中的作用机制有助于解释疾病的发展机制,为疾病的治疗提供依据。文中就T-bet在乙型肝炎中的作用机制作一综述。     

疗养院体检服务质量评价系统的实践

本文详细介绍了疗养院体检服务质量评价系统的设计目的 、设计方法和主要实现功能.该系统的应用,使体检人员的意见得到及时反馈,有助于管理者对各科室及员工的服务水准和存在问题进行判断总结,从而促进了疗养院体检服务质量水平的进一步提高.