Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor‐bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO‐1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO‐1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF‐induced hyperpermeability. Further investigations revealed that VEGF‐induced occludin phosphorylation at Ser‐490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin‐proteasome system. In conclusion, primary tumor‐secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF‐induced vascular hyperpermeability in the lung premetastatic niche.     

艾灸治疗原发性骨质疏松症患者腰背疼痛有效性的系统评价

[目的]系统评价艾灸对原发性骨质疏松症患者腰背痛的有效性。[方法]计算机检索中国知网(CNKI),万方数据库(Wan Fang),维普全文期刊数据库(VIP),中国生物医学文献数据库(CBM),Pub Med,Embase,Web of Science和Cochrane library等数据库,查找治疗组以艾灸为主,对照组以药物治疗原发性骨质疏松症腰背痛的随机对照试验,检索时限截至2017年12月。采用Revman 5.3软件进行Meta分析。[结果]最终纳入11篇文献,包括842例患者,文献质量评价显示文献质量偏低。Meta分析结果显示:艾灸组与药物组相比,在改善腰背痛疼痛视觉模拟评分法(VAS)评分、中医证候疗效、中医治疗有效率上,艾灸组优于药物组[(SMD=-1.99,95%CI:-2.76,-1.22,P0.000 01),(SMD=-0.72,95%CI:-1.07,-0.36,P0.000 1),(RR=1.15,95%CI:1.06,1.24,P=0.000 5)]。在临床疗效、改善腰椎骨密度方面与药物组相比不具有统计学意义[(RR=1.25,95%CI:0.90,1.73,P=0.18),(SMD=0.30,95%CI:-0.37,0.96,P=0.38)]。[结论]现有的研究结果表明,艾灸治疗原发性骨质疏松症腰背痛的疗效优于药物,并且可以与药物协同使用增效;在改善腰椎骨密度方面艾灸的疗效可能与药物相当。但是由于纳入文献质量偏低,仍需更高质量的随机对照试验来证实。     

���޴����Ķ�L1210����С���������ߵij����о�

??OBJECTIVE To explore the antitumor effect and immunity change of Periplaneta americana C??3 and related synthetic peptide HFDT1 in mice and to provide a base for clinical application of the materials. METHODS Sixty BALB/c mouse tumor model with leukemia L1210 were established and divided into five groups. The mice were treated with Periplaneta americana C??3 high dose, low dose, HFDT1, CTX and normal saline for 10 d, respectively. Twelve mice were as normal control group. The tumor inhibition rates and weight of body were observed in different groups. Then the results were observed including thymus and spleen index, the numbers of immune cells in peripheral blood, the ratio of splenic total lymphocytes, splenic B cell(CD45R⁺)and T cell(CD3⁺), T cell subset(CD3⁺CD4⁺ and CD3⁺CD8⁺ T cell), and the levels of IgG, IgA and IgM in serum through weight, auto-analysis of blood cell, flow cytometry, sandwich-antibody ELISA from thymus, spleen, peripheral blood in the mice. RESULTS The results showed that C??3 and HFDT1 inhibited the growth of mouse L1210 tumor and maintained the mouse weights. They increased the mouse thymus indexes and spleen indexes effectively and the numbers of peripheral blood immune cells. They maintained the spleen lymphocyte and regulated the ratio of T and B lymphocytes, CD3⁺CD4⁺ T cell and CD3⁺CD8⁺T cell. They increased the levels of serum IgG, IgA and IgM. CONCLUSION Periplaneta americana extract C??3 and related synthetic peptide HFDT1 have a strong inhibition effect to tumor. The antitumor effect of C??3 and HFDT1 may be achieved through to improve immune function. They are hoped to become efficient and low toxicity antitumor drugs. Especially HFDT1, it has an extensive application because it can be synthesized by artificial methods.     

A General Moving Mesh Framework in 3D and Its Application for Simulating the Mixture of Multi-Phase Flows

In this paper, we present an adaptive moving mesh algorithm for meshes of unstructured polyhedra in three space dimensions. The algorithm automatically adjusts the size of the elements with time and position in the physical domain to resolve the relevant scales in multiscale physical systems while minimizing computational costs. The algorithm is a generalization of the moving mesh methods based on harmonic mappings developed by Li et al. [J. Comput. Phys., 170 (2001), pp. 562-588, and 177 (2002), pp. 365-393]. To make 3D moving mesh simulations possible, the key is to develop an efficient mesh redistribution procedure so that this part will cost as little as possible comparing with the solution evolution part. Since the mesh redistribution procedure normally requires to solve large size matrix equations, we will describe a procedure to decouple the matrix equation to a much simpler block-tridiagonal type which can be efficiently solved by a particularly designed multi-grid method. To demonstrate the performance of the proposed 3D moving mesh strategy, the algorithm is implemented in finite element simulations of fluid-fluid interface interactions in multiphase flows. To demonstrate the main ideas, we consider the formation of drops by using an energetic variational phase field model which describes the motion of mixtures of two incompressible fluids. Numerical results on two- and three-dimensional simulations will be presented.     

Behavioral Dyscontrol Scale-Electronic Version: first examination of reliability, validity, and incremental utility

Behavioral Dyscontrol Scale (BDS) is a clinical measure previously shown to be related to frontal lobe integrity, executive abilities, and functional independence. Electronic version of the scale (BDS-EV) was developed and its reliability and validity were examined. The BDS-EV, the original BDS, and a brief battery of traditional clinical tests were administered to 55 community-dwelling adults ages 18 to 68. The results yielded high internal consistency and provided support for convergent, discriminant, and incremental validity. Overall, the results demonstrate the feasibility of converting the BDS into an electronic instrument and support continued research and development of this instrument.     

Microtubules are critical for radial glial morphology: possible regulation by MAPs and MARKs

Radial glia are a polarized cell type that in most neural regions appear only transiently during development. They have long been recognized as glia or glial progenitors that support neuronal migration. Recent evidence indicates that radial glia also give rise to neurons and appear to be a major population of dividing precursor cells in the embryonic cortical ventricular zone. Radial glia extend long processes from the ventricular zone to the pial surface that provide guides for neuronal migration. We reasoned that the unique morphology of radial glia is due to the composition and organization of their cytoskeleton. In this present study, we have used C6-R, a radial glial-like cell line and isolated perinatal cerebellar radial glia to ask what are the critical cytoskeletal elements in radial glial cells and how they are regulated. Treatments with nocodazole and cytochalasin D showed that microtubules, but not microfilaments, are critical for the polarized morphology of radial glia. In addition, quantitative real-time PCR indicated that certain mRNAs specific for microtubule-associated proteins (MAPs) are selectively expressed in radial glia. These results together with the known ability of microtubule affinity-regulating kinases to regulate microtubule organization suggest that microtubules and MAPs are critical for the morphology of radial glia.     

Behavioral Dyscontrol Scale deficits among traumatic brain injury patients, part I: Validation with nongeriatric patients

The Behavioral Dyscontrol Scale is a measure of executive abilities initially designed to predict functional independence in geriatric populations. The current study examined the utility of two Behavioral Dyscontrol Scale (BDS) scoring systems in a nongeriatric sample. The BDS was administered to 49 TBI patients undergoing inpatient and outpatient rehabilitation. The results demonstrate slightly greater utility of the BDS-II scoring system, and support clinical utility of the instrument with nongeriatric patients. Specifically, the Motor Programming Factor and Environmental Independence Factor were more impaired among patients with severe, as compared to mild to moderate, TBIs. In contrast, the Fluid Intelligence Factor was more impaired among patients with frontal, as compared to nonfrontal, injuries. However, when patients were categorized by severity, lesion location differences on the BDS total score and factors were found only for patients with mild to moderate injuries. Similarly, when patients were categorized by lesion location, severity effects were only present among the nonfrontal group. Receiver Operating Characteristic curves demonstrated sensitivity and specificity rates that ranged from 60% to 100% for clinically meaningful cutting scores.     

Expression of kynurenine aminotransferases in the rat retina during development

The study investigates the cellular expression of kynurenine aminotransferases (KAT I and II) in the rat retina during development. At P1 (the day of birth) and P7 (the 7th day after birth), KAT I expression was observed in the inner plexiform layer (IPL), the fiber layer (FL), and in vertically running processes in the ganglion cell layer (GCL) (but not in the cell bodies). At P14 (the 14th day after birth) a strong KAT I immunoreactivity was observed in Müller cell endfeet. KAT II was expressed in the IPL, the FL, and in cells in the GCL at P1 and P7. From P14 on, KAT II expression in the IPL decreased. Double labeling revealed that KAT I was expressed in Müller cell endfeet, whilst KAT II both on retinal ganglion cells (RGC) and Müller cell endfeet. In conclusion, KAT I and II are present in the rat retina during development. The heterogeneity of the KAT developmental profiles possibly reflects a neuromodulatory role in the retinal differentiation.     

Age-dependent decrease of retinal kynurenate and kynurenine aminotransferases in DBA/2J mice, a model of ocular hypertension

The study examines age-dependent changes of kynurenic acid (KYNA) content and kynurenine aminotransferases (KAT I and KAT II) celluar expression in the retinas of DBA/2J mice. Retinas were obtained from DBA/2J mice of different ages (3, 6 and 11 months). C57BL6 mice were used as controls. As measured with HPLC, KYNA content decreased (p < 0.01) in the retinas of 6-month-old DBA/2J mice and continued to decrease (p < 0.0074) in the retinas of 11-month-old animals compared to the controls. Immunohistochemistry showed that expression of both KAT I and KAT II decreased markedly in the retinas of 11-month-old DBA/2J mice compared to controls. The impairment in KYNA biosynthesis in the retinas of DBA/2J mice may be one of the mechanisms of retinal neurodegeneration related to ocular hypertension.