Kaposi’s Sarcoma Lesion Progression in BKV-Tat Transgenic Mice Is Increased by Inflammatory Cytokines and Blocked by Treatment with Anti-Tat Antibodies

Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved AIDS-KS incidence and course, it continues to be an incurable disease and the development of new rational targeted therapies is warranted. We used the BKV/Tat transgenic mouse model to evaluate the effects of IC and anti-Tat antibodies (Abs) treatment on KS-like lesions arising in BKV/Tat mice. We demonstrated here that IC-treatment increases the severity and delays the regression of KS-like lesions. Further, anti-Tat Abs reduced KS-like lesion severity developing in IC-treated mice when anti-Tat Abs were administered at an early-stage of lesion development as compared to more advanced lesions. Early anti-Tat Abs treatment also accelerated KS-like lesion regression and reduced the rate of severe-grade lesions. This effect was more evident in the first weeks after Ab treatment, suggesting that a longer treatment with anti-Tat Abs might be even more effective, particularly if administered just after lesion development. Although preliminary, these results are encouraging, and the approach deserves further studies for the development of anti-Tat Ab-based therapies for AIDS-KS. Clinical studies specifically addressing the effect of anti-Tat antibodies in treating AIDS-KS are not yet available. Nevertheless, the effectiveness of anti-Tat antibodies in controlling HIV/AIDS progression, likely due to the neutralization of extracellular Tat activities, is suggested by several cross-sectional and longitudinal clinical studies, indicating that anti-Tat Ab treatment or Tat-based vaccines may be effective to treat AIDS-KS patients or prevent the tumor in individuals at risk.     

我国上市中小企业成长性模型实证研究

针对我国上市中小企业成长性问题,采用关联度分析方法,从研究不同的成长性理论入手,通过对影响企业成长性主要因素的分析,建立一套合理科学的上市中小企业成长性评价指标体系.根据该指标体系,运用突变级数法建立了成长性评价模型.最后,对选取的30家上市中小企业进行成长性排名的实证研究,结果验证了该评价体系的有效性.     

Age- and Stage-Dependent Prostate Cancer Aggressiveness Associated with Differential Notch Signaling

Prostate cancer (PC) remains a worldwide challenge, as does the question of how to distinguish its indolent from its aggressive form to reconcile proper management of the disease with age-related life expectations. This study aimed to differentiate the Notch-driven course of PC regarding patients’ ages and stage of their disease. We analyzed 397 PC samples split into age subgroups of ≦55, 60–70, and >70 years old, as well as early vs. late stage. The clinical association of Notch signaling was evaluated by DFS and UpSet analyses. The clustering of downstream effectors was performed with ExpressCluster. Finally, for the most relevant findings, functional networks were constructed with MCODE and stringApp. The results have been validated with an independent cohort. We identified specific patterns of Notch expression associated with unfavorable outcomes, which were reflected by entering into a hybrid epithelial/mesenchymal state and thus reaching tumor plasticity with its all consequences. We characterized the molecular determinants of the age-related clinical behavior of prostate tumors that stem from different invasive properties depending on the route of the EMT program. Of the utmost relevance is the discovery of age- and stage-specific combinations of the Notch molecules predicting unfavorable outcomes and constituting a new prognostic and therapeutic approach for PCs.     

Hypoxia and Ezrin Expression in Primary Melanoma Have High Prognostic Relevance

Hypoxia affects tumor aggressiveness and activates pathways associated with epithelial mesenchymal transition (EMT) which are crucial for tumor progress. In this study, the correlation of hypoxia and EMT with sentinel lymph node status and tumor-specific survival was investigated in primary melanomas. CD34 for capillary count and Hypoxia inducible factor-1α (HIF-1α) as hypoxia indicators as well as Ezrin and L1-Cell Adhesion Molecule (L1CAM), both critical proteins contributing to EMT, were analyzed using immunohistochemistry in 49 melanoma patients with long follow-up (F/U, mean 110 months; range 12–263 months). We found a significant correlation between Breslow tumor thickness and Ezrin expression (p = 0.018). L1CAM expression in primary melanoma was significantly associated with HIF-1α expression (p < 0.0001) and sentinel lymph node metastasis (p = 0.011). Furthermore, low capillary count, reflecting hypoxic condition, was significantly associated with Ezrin expression (p = 0.047) and decreased tumor-specific survival (p = 0.035). In addition, patients with high Ezrin expression in their primary melanoma had a dramatic loss of life early in their F/U period (mean survival time 29 months; range 15–44 month). Our results highlight the relevance of Ezrin, L1CAM and HIF-1α as prognostic markers in melanoma patients. Additionally, we demonstrate that hypoxia in primary melanoma affects EMT and is at least partly responsible for early metastatic dissemination.     

Genetic Polymorphisms of lncRNA LINC00673 as Predictors of Hepatocellular Carcinoma Progression in an Elderly Population

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations.     

Increased Prevalence of Unstable HLA-C Variants in HIV-1 Rapid-Progressor Patients

HIV-1 infection in the absence of treatment results in progression toward AIDS. Host genetic factors play a role in HIV-1 pathogenesis, but complete knowledge is not yet available. Since less-expressed HLA-C variants are associated with poor HIV-1 control and unstable HLA-C variants are associated with higher HIV-1 infectivity, we investigated whether there was a correlation between the different stages of HIV-1 progression and the presence of specific HLA-C allotypes. HLA-C genotyping was performed using allele-specific PCR by analyzing a treatment-naïve cohort of 96 HIV-1-infected patients from multicentric cohorts in the USA, Canada, and Brazil. HIV-1-positive subjects were classified according to their different disease progression status as progressors (Ps, n = 48), long-term non-progressors (LTNPs, n = 37), and elite controllers (ECs, n = 11). HLA-C variants were classified as stable or unstable according to their binding stability to β2-microglobulin/peptide complex. Our results showed a significant correlation between rapid progression to AIDS and the presence of two or one unstable HLA-C variants (p-value: 0.0078, p-value: 0.0143, respectively). These findings strongly suggest a link between unstable HLA-C variants both at genotype and at allele levels and rapid progression to AIDS. This work provides further insights into the impact of host genetic factors on AIDS progression.     

Kininogen及其在鱼类中的研究进展

本文首先介绍了半胱氨酸蛋白酶抑制因子超家族中kininogen(家族III)及其各结构域的功能。在此基础上,阐述了鱼类kininogen在分离纯化、活性和结构特征的研究进展。最后,分析探讨了鱼类kininogen在食品、医药领域的应用前景,并展望了鱼类加工下脚料中kininogen的开发利用方向。      

特高压直流输电线路雷击上行先导竞机制(英文)

Research on the lightning shielding failure characteristics of UHVDC transmission lines is important for adequate transmission line protection and safe operation of a power grid.Focusing the competition characteristics of upward leaders in the lightning attachment process,this work provides technical reference for efficient evaluations of lightning shielding failures and reliable lightning protection designs of UHVDC transmission lines.The charge simulation method is employed to calculate electric field distributions.Based on the calculation and some data obtained by recent long-gap discharge and lightning observations,the effect of several upward leaders starting from UHVDC transmission lines on lightning attachment processes is studied by numerical simulation.The results show that the upward leader inception is delayed,the propagation velocity is smaller,and the propagation direction of the upward leader is changed with interaction among all upward leaders,which influences the selection of lightning striking point.Therefore,in order to improve the accuracy of calculating the lightning shielding failure rate of UHVDC transmission lines,the interaction characteristics of upward leaders should be taken into account.In addition,an analysis of the influence of operating voltage and the protection angle of UHVDC transmission lines based on competition mechanism of upward leaders is made.It is found that the existence of operating voltage mainly affects the ability of the conductor and the overhead ground wire at the same side to incept upward leaders,while the protection angle mainly affects the position of the "starting points" of upward leaders.The results indicate that positive polar conductors should be installed closer to hillsides and the negative protection angle of towers is suggested.     

考虑随机性分布式电源的配电系统潮流计算简

配电系统中风力发电以及光伏发电等具有随机性的分布式电源容量的不断增加,使配电系统潮流变化具有一定的随机性。根据风电系统以及光伏系统的变化规律建立了风电以及光伏的随机等效模型,利用三点估计法进行了含随机分布式电源的概率潮流计算,并利用Gram Charlier级数得到相关变量的概率密度分布函数,通过对IEEE33节点进行仿真说明了方法的可行性。     

Numerical three-dimensional modeling of earthen dam piping failure

A physically-based numerical three-dimensional earthen dam piping failure model is developed for homogeneous and zoned soil dams. This model is an erosion model, coupled with force/moment equilibrium analyses. Orifice flow and two-dimensional (2D) shallow water equations (SWE) are solved to simulate dam break flows at different breaching stages. Erosion rates of different soils with different construction compaction efforts are calculated using corresponding erosion formulae. The dam's real shape, soil properties, and surrounding area are programmed. Large outer 2D-SWE grids are used to control upstream and downstream hydraulic conditions and control the boundary conditions of orifice flow, and inner 2D-SWE flow is used to scour soil and perform force/moment equilibrium analyses. This model is validated using the European Commission IMPACT (Investigation of Extreme Flood Processes and Uncertainty) Test #5 in Norway, Teton Dam failure in Idaho, USA, and Quail Creek Dike failure in Utah, USA. All calculated peak outflows are within 10% errors of observed values. Simulation results show that, for a V-shaped dam like Teton Dam, a piping breach location at the abutment tends to result in a smaller peak breach outflow than the piping breach location at the dam's center; and if Teton Dam had broken from its center for internal erosion, a peak outflow of 117 851 m³/s, which is 81% larger than the peak outflow of 65 120 m³/s released from its right abutment, would have been released from Teton Dam. A lower piping inlet elevation tends to cause a faster/earlier piping breach than a higher piping inlet elevation.