The presented article focuses on the relationship between social exclusion and the transport geographical characteristics which are considered as instrumental in the development of social exclusion, and also as a negative feature that can even deepen the exclusion. In the first part, the author generally defines and examines the concept of social exclusion as a selectively operating process of differentiation, the way it has been perceived over time and its individual aspects with an emphasis on the spatial dimension. The second part of the article is devoted to the conditional relationship between transportation and social exclusion. Besides the description of this process of exclusion, which is transport related, there is a discussion of the role of transport (in)accessibility and characteristics of personal mobility as a crucial factors which cause or intensify the exclusion. On the other hand it also offers a chance to reintegrate individuals into society.
The intestinal mucosa normally displays minimal inflammation despite the close proximity between mucosal macrophages and lumenal bacteria. Macrophages interact with bacteria and their products through CD14, a surface receptor involved in the response to LPS, and CD89, the receptor for IgA (FcαR). Here we show that resident macrophages isolated from normal human intestine lack CD14 and CD89. The absence of CD14 and CD89 was not due to the isolation procedure or mucosal cell products, but was evident at the transcriptional level, as the macrophages expressed neither CD14- nor CD89-specific mRNAs, but did express Toll-like receptor 2 and 4 transcripts. Consistent with their CD14− phenotype, lamina propria macrophages displayed markedly reduced LPS-induced cytokine production and LPS-enhanced phagocytosis. In addition, IgA-enhanced phagocytosis was sharply reduced in lamina propria macrophages. Thus, the absence of CD14 and CD89 on resident intestinal macrophages, due to down-regulated gene transcription, causes down-modulated LPS- and IgA-mediated functions and probably contributes to the low level of inflammation in normal human intestinal mucosa.
The levels of interleukin (IL)-1, IL-6, IL-8, IL-10, and transforming growth factor-beta in sera and genital tract secretions from women with gonococcal cervicitis and other genital infections were examined. Cytokines were not elevated in genital secretions from gonococcus-infected compared with uninfected patients. The level of serum IL-6 was higher in gonococcus-infected than in uninfected patients at recruitment. Serum, but not local, IL-1 and IL-6 levels were elevated in patients concomitantly infected with Trichomonas vaginalis or Chlamydia trachomatis in addition to Neisseria gonorrhoeae compared with levels in patients infected with any single organism. Concomitant infection altered neither the total immunoglobulin concentrations nor the levels of antigonococcal antibodies in serum or local secretions. The results suggest that N. gonorrhoeae induces only a limited cytokine and antibody response during uncomplicated cervical infections; however, the presence of other sexually transmitted disease-causing organisms can alter the systemic cytokine but not the antigonococcal antibody levels.
Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically ''tumor-free'' surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumorfree rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P < 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P < 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTORactivated residual cells. [Cancer Res 2007;67(5):2160-8]
Adenoviral vectors have been exploited for a wide range of gene therapy applications. Direct genetic modification of the adenovirus capsid proteins has been employed to achieve alteration of vector tropism. We have defined the carboxy-terminus of the minor capsid protein pIX as a locus capable of presenting incorporated ligands on the virus capsid surface. Thus, we sought to exploit the possibility of incorporating functional proteins at pIX. In our current study, we incorporated the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) within pIX to determine if a larger protein of this type could retain functionality in this context. Our study herein clearly demonstrates our ability to rescue viable adenoviral particles that display functional HSV-1 TK as a component of their capsid surface. DNA packaging and cytopathic effect were not affected by this genetic modification to the virus, while CAR-dependent binding was only marginally affected. Using an in vitro [3H]-thymidine phosphorylation assay, we demonstrated that the kinase activity of the protein IX-TK fusion protein incorporated into adenoviral virions is functional. Analysis of cell killing after adenovirus infection showed that the protein IX-TK fusion protein could also serve as a therapeutic gene by rendering transduced cells sensitive to gancyclovir. Using 9-[4-[18F]-fluoro-3-(hydroxymethyl)butyl]guanine ([18F]-FHBG; a positron-emitting TK substrate), we demonstrated that we could detect specific cell binding and uptake of adenoviral virions containing the protein IX-TK fusion protein at 1 h post-infection. Our study herein clearly demonstrates our ability to rescue viable adenoviral particles that display functional HSV-1 TK as a component of their capsid surface. The alternative display of HSV-1 TK on the capsid may offer advantages with respect to direct functional applications of this gene product. In addition, the determination of an expanded upper limit of incorporable proteins on pIX highlights its unique utility as a locus for placement of functional vector constructs.
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