Comparison of characteristics of esophageal squamous cell carcinoma associated with head and neck cancer and those with gastric cancer

In ongoing reviews of 339 patients with surgically treated primary squamous cell carcinoma, there were 19 (5.6%) with concurrent gastric cancer and 11 (3.2%) with head and neck cancer. The incidences of intra-esophageal multiple occurrence of esophageal cancer are 27.3% and 26.3% in those with associated head and neck cancer and gastric cancer, respectively, and higher than 7.1% in those without such a concurrent cancer. There was no difference in the clinicopathological characteristics of those with concurrent head and neck and gastric cancers, except for the higher incidence of metachronous occurrence in the former. These findings suggest that, in cases of esophageal cancer associated with concurrent head and neck cancer and gastric cancer, intraesophageal multiplicity of the esophageal carcinoma is frequent and that preoperative serial evaluations is most important to design treatment and estimate the prognosis.     

Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production—Flow cytometry and mathematical modeling

Cell culture-based influenza vaccine manufacturing is of growing importance. Depending on virus strains, differences in infection dynamics, virus-induced apoptosis, cell lysis and virus yields are observed. Comparatively little is known concerning details of virus–host cell interaction on a cellular level and virus spreading in a population of cells in bioreactors. In this study, the infection of MDCK cells with different influenza A virus strains in lab-scale microcarrier culture was investigated by flow cytometry. Together with the infection status of cells, virus-induced apoptosis was monitored. A mathematical model has been formulated to describe changes in the concentration of uninfected and infected adherent cells, dynamics of virus particle release (infectious virions, hemagglutinin content), and the time course of the percentage composition of the cell population.     

A recycling framework for the construction of Bonferroni‐based multiple tests

In this paper we describe Bonferroni‐based multiple testing procedures (MTPs) as strategies to split and recycle test mass. Here, ‘test mass’ refers to (parts of) the nominal level α at which the family‐wise error rate is controlled. Briefly, test mass is split between different null hypotheses, and whenever a null hypothesis is rejected, the part of α allocated to it may be recycled to the testing of other hypotheses. These recycling MTPs are closed testing procedures based on raw p‐values associated with testing the individual null hypotheses, and the class of such MTPs includes, for example, serial and parallel gatekeeping, fallback and Holm procedures. Graphical displays and a concise algebraic notation are provided for such MTPs. This recycling approach has pedagogical advantages and may facilitate the tailoring of MTPs for different purposes. Copyright © 2009 John Wiley & Sons, Ltd.     

肺血栓栓塞症危险因素分析

目的探讨肺栓塞的独立危险因素,明确每项危险因素所起作用大小。方法放射性核素肺通气／灌注扫描和（或）螺旋CT检查并结合临床资料确诊的肺血栓栓塞症病人71例为病例组,性别、年龄匹配的部分住院病人及门诊健康体检者71例为对照组。详细记录文献上提及的相关危险因素,同时对部分因素进行了控制。两组入选者均查血常规,在空腹12h后抽静脉血测血三酰甘油、胆固醇、抗凝血酶Ⅲ（AT-Ⅲ）、纤维蛋白原、纤溶酶原等生化指标,利用SPSS进行t检验、x^2检验及Logistic回归分析。结果肺栓塞的独立危险因素包括下肢静脉血栓形成（OR 44．427,95％ CI 10．105～195．317,P〈0．05）,手术（OR 3．407,95％CI 1．042～11．136,P〈0．05）,纤维蛋白原（OR 1．717,95％CI 1．250～3．567,P〈0．05）,胆固醇（OR 1．678,95％CI 1．287～3．672,P〈0．05）,纤溶酶原（OR 1．022,95％CI 1．000～1．121,P〈0．05）,吸烟指数（OR 1．003,95％ CI 1．001～1．006,P〈0．05）。结论下肢深静脉血栓形成、手术、高纤维蛋白原、胆固醇、纤溶酶原、吸烟是肺栓塞的独立危险因素,肺栓塞发病与多种因素有关。     

大肠埃希菌噬菌体的分离鉴定及其生物学特性研究

目的通过分离鉴定大肠埃希菌噬菌体,研究其生物学特性。方法利用噬菌斑法从环境污水中分离和鉴定大肠埃希菌噬菌体,采用负染法电镜观察噬菌体的形态和大小;提取噬菌体的基因组并进行酶切电泳分析,测定噬菌体感染复数并观察其一步生长曲线。结果通过噬菌斑法分离出9株大肠埃希菌噬菌体。电镜显示,噬菌体头部呈立体对称,有一长尾。琼脂糖凝胶电泳显示,噬菌体基因组大小约30kb。生长曲线表明噬菌体感染宿主菌的潜伏期为23min,爆发时间为39min,裂解量为78。结论9株大肠埃希菌噬菌体中有6株具有较广的噬菌谱,潜伏期短,裂解量明显,为深入研究大肠埃希菌噬菌体的生物学特性及其功能提供了依据。     

Chlamydia trachomatis inhibits telomeric DNA damage signaling via transient hTERT upregulation

Epidemiological data exist to support a positive association between Chlamydia trachomatis (Ctr) infection and gynecological cancers; however, putative cellular mechanisms for this association are lacking. Here, we identified Ctr-induced perturbations to host cell phenotypes in vitro that persisted after clearance of infection and could directly contribute to host cell transformation. In particular, human telomerase catalytic subunit (hTERT) mRNA expression and catalytic subunit activity were increased in acute infected late passage IMR90E1A cells. hTERT upregulation was accompanied by recruitment of ceramide, a known regulator of hTERT, to the chlamydial inclusion and was abrogated following doxycycline-mediated infection clearance. In cells cleared of Ctr infection, average telomere length was slightly increased and immunofluorescence staining of the DNA damage marker γH2A.X was reduced after clearance of infection compared with cells that had not been infected. Reduced p53 binding to the promoter of the cell cycle checkpoint regulator p21 was also detected in cells cleared of infection and p21 levels were reduced; moreover, this cell population exhibited increased resistance to etoposide-induced DNA damage. Thus, Ctr infection altered cell aging and survival pathways, which persisted after infection clearance. Cells that survive infection are likely to exhibit altered physiology, as evidenced by an increased resistance to DNA damage-induced apoptosis, which may support cellular transformation.     

Statistical planning in confirmatory clinical trials with multiple treatment groups,multiple visits,and multiple endpoints

ABSTRACT

Multiplicity issues can be multidimensional: A confirmatory clinical trial may be designed to have efficacy assessed with two or more primary endpoints, for multiple dose groups, and at several post-baseline visits. Controlling for multiplicity in this situation is challenging because there can be a hierarchy with respect to some but not all measurements. If the higher dose is considered more efficacious, multiplicity approach may evaluate the higher dose with higher priority through a fixed sequential testing framework for dose assessments in combination with a Hochberg approach for endpoints. The lower dose is only assessed when the higher dose has significant results, which reduces the power for detecting signals in the lower dose group. However, in some instances the higher dose may associate with tolerability or safety concerns that preclude regulatory approval. A real confirmatory clinical trial with such challenges is provided as an illustrative example. We discuss closed testing procedures based on multi-way averages of comparisons for this complex multiplicity situation through illustrative case analyses and a simulation study. Such strategies manage the higher dose and the lower dose with equal priority, and they enable evaluation of the multiple endpoints at multiple visits collectively with power being reasonably high.     

Differing roles of protein kinase C-zeta in disruption of tight junction barrier by enteropathogenic and enterohemorrhagic Escherichia coli

BACKGROUND & AIMS: Enteropathogenic Escherichia coli and enterohemorrhagic E. coli harbor highly homologous pathogenicity islands yet show key differences in their mechanisms of action. Both disrupt host intestinal epithelial tight junctions, but the effects of enteropathogenic E. coli are more profound than those of enterohemorrhagic E. coli. The basis for this is not understood. The atypical protein kinase C isoform, protein kinase C-zeta, associates with and regulates the tight junction complex. The aim of this study was to compare the role of protein kinase C-zeta in the disruption of tight junctions after infection with enteropathogenic E. coli and enterohemorrhagic E. coli. METHODS: Model intestinal epithelial monolayers infected by enteropathogenic E. coli or enterohemorrhagic E. coli were used for these studies. RESULTS: Neither bisindolylmaleimide nor G?6976, which block several protein kinase C isoforms but not protein kinase C-zeta, protected against the decrease in transepithelial electrical resistance after enteropathogenic E. coli infection. Rottlerin at concentrations that block novel and atypical isoforms, including protein kinase C-zeta, significantly attenuated the decrease in transepithelial electrical resistance. The specific inhibitory peptide, myristoylated protein kinase C-zeta pseudosubstrate, also significantly decreased the enteropathogenic E. coli -associated decrease in transepithelial electrical resistance and redistribution of tight junction proteins. In contrast to enteropathogenic E. coli, the level of protein kinase C-zeta enzyme activity stimulated by enterohemorrhagic E. coli was transient and minor, and protein kinase C-zeta inhibition had no effect on the decrease in transepithelial electrical resistance or the redistribution of occludin. CONCLUSIONS: The differential regulation of protein kinase C-zeta by enteropathogenic E. coli and enterohemorrhagic E. coli may in part explain the less profound effect of the latter on the barrier function of tight junctions.     

Functional conservation of suppressors of cytokine signaling proteins between teleosts and mammals: Atlantic salmon SOCS1 binds to JAK/STAT family members and suppresses type I and II IFN signaling

Suppressor of cytokine signaling (SOCS) proteins are crucially involved in the control of inflammatory responses through their impact on various signaling pathways including the JAK/STAT pathway. Although all SOCS protein family members are identified in teleost fish, their functional properties in non-mammalian vertebrates have not been extensively studied. To gain further insight into SOCS functions in bony fish, we have identified and characterized the Atlantic salmon (Salmo salar) SOCS1, SOCS2 and CISH genes. These genes exhibited sequence conservation with their mammalian counterparts and they were ubiquitously expressed. SOCS1 in mammalian species has been recognized as a key negative regulator of interferon (IFN) signaling and recent data for the two model fish Tetraodon (Tetraodon nigroviridis) and zebrafish (Danio rerio) suggest that these functions are conserved from teleost to mammals. In agreement with this we here demonstrate a strong negative regulatory activity of salmon SOCS1 on type I and type II IFN signaling, while SOCS2a and b and CISH only moderately affected IFN responses. SOCS1 also inhibited IFNγ-induced nuclear localization of STAT1 and a direct interaction between SOCS1 and STAT1 and between SOCS1 and the Tyk2 kinase was found. Using SOCS1 mutants lacking either the KIR domain or the ESS, SH2 and SOCS box domains showed that all domains affected the ability of SOCS1 to inhibit IFN-mediated signaling. These results are the first to demonstrate that SOCS1 is a potent inhibitor of IFN-mediated JAK-STAT signaling in teleost fish.