Interleukin-6 -572G/C polymorphism and prostate cancer susceptibility.

Strong evidence suggests that cancer-associated inflammation promotes tumor growth and progression, and interleukin-6 (IL6) is an important modulator of inflammation. However, the roles of IL6 and mutations of its corresponding gene in prostate cancer have not been clearly documented. We retrieved data from the Oncomine database concerning IL6 expression in prostate cancer and its role in prostate-specific antigen (PSA) recurrence. We also performed a case-control study of the IL6 -572G/C polymorphism (rs1800796) in 236 sporadic prostate cancer patients and 256 healthy controls from a southern Han Chinese population. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between rs1800796 and prostate cancer susceptibility. A dual-luciferase reporter assay was used to test the transcriptional activity of the IL6 promoter G and C alleles. IL6 was overexpressed in prostate cancer tissues compared to normal tissues, especially in those with higher Gleason scores. Moreover, elevated IL6 expression was associated with high PSA recurrence rate in Oncomine data. Our case-control study demonstrated that compared with the -572C allele, the -572G allele conferred a borderline increased risk of prostate cancer (OR = 1.31, 95%CI = 0.99-1.74, P = 0.061). This was more pronounced in the subgroup of individuals having never smoked (OR = 1.85, 95%CI = 1.07-3.22). Moreover, the G allele showed increased activity relative to the C allele in the dual-luciferase reporter assay. Our results suggest that the -572G/C polymorphism may be associated with IL6 expression, which in turn plays a role in prostate cancer development.

Statistical switching kinetics of ferroelectrics.

By assuming a more realistic nucleation and polarization reversal scenario we build a statistical switching model for polycrystalline ferroelectrics, which is different from both the Kolmogorov-Avrami-Ishibashi (KAI) model and the nucleation-limited-switching model. After incorporating a time-dependent depolarization field, this model gives a good explanation of the retardation behavior in polycrystalline thin films at medium or low fields, which cannot be described using the traditional KAI model. This model predicts n = 1 for polycrystalline thin films at high fields or ceramic bulks in the ideal case, in good agreement with the experimental data previously published.

Lipoprotein(a) vascular accumulation in mice. In vivo analysis of the role of lysine binding sites using recombinant adenovirus.

Although the mechanism by which lipoprotein(a) [Lp(a)] contributes to vascular disease remains unclear, consequences of its binding to the vessel surface are commonly cited in postulated atherogenic pathways. Because of the presence of plasminogen-like lysine binding sites (LBS) in apo(a), fibrin binding has been proposed to play an important role in Lp(a)'s vascular accumulation. Indeed, LBS are known to facilitate Lp(a) fibrin binding in vitro. To examine the importance of apo(a) LBS in Lp(a) vascular accumulation in vivo, we generated three different apo(a) cDNAs: (a) mini apo(a), based on wild-type human apo(a); (b) mini apo(a) containing a naturally occurring LBS defect associated with a point mutation in kringle 4-10; and (c) human- rhesus monkey chimeric mini apo(a), which contains the same LBS defect in the context of several additional changes. Recombinant adenovirus vectors were constructed with the various apo(a) cDNAs and injected into human apoB transgenic mice. At the viral dosage used in these experiments, all three forms of apo(a) were found exclusively within the lipoprotein fractions, and peak Lp(a) plasma levels were nearly identical (approximately 45 mg/dl). In vitro analysis of Lp(a) isolated from the various groups of mice confirmed that putative LBS defective apo(a) yielded Lp(a) unable to bind lysine-Sepharose. Quantitation of in vivo Lp(a) vascular accumulation in mice treated with the various adenovirus vectors revealed significantly less accumulation of both types of LBS defective Lp(a), relative to wild-type Lp(a). These results indicate a correlation between lysine binding properties of Lp(a) and vascular accumulation, supporting the postulated role of apo(a) LBS in this potentially atherogenic characteristic of Lp(a).

Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice.

Lipoprotein(a) contributes to the development of atherosclerosis through the binding of its plasminogen-like apolipoprotein(a) component to fibrin and other plasminogen substrates. Apolipoprotein(a) contains a major lysine binding site in one of its kringle domains. Destruction of this site by mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin. Transgenic mice expressing this mutant form of apolipoprotein(a) as well as mice expressing wild-type apolipoprotein(a) have been created in an inbred mouse strain. The wild-type apolipoprotein(a) transgenic mice have a fivefold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared with the lysine binding site mutant strain and to nontransgenic littermates. The results demonstrate the key role of this lysine binding site in the pathogenic activity of apolipoprotein(a) in a murine model system.

Inverse correlation between CD4+ CD25high CD127low/- regulatory T-cells and serum immunoglobulin A in patients with new-onset ankylosing spondylitis.

This study investigated the role of regulatory T (T(reg)) cells in patients with new-onset, treatment-naïve ankylosing spondylitis (AS). Levels of CD4(+)CD25(high)CD127(low/-) T(reg) cells in the peripheral blood of 14 AS patients and 18 age-matched healthy volunteers were investigated by flow cytometry and correlations with serum levels of immunoglobulin A (IgA) and AS activity, as assessed by the Bath AS Disease Activity Index (BASDAI), were analysed. The number of peripheral blood CD4(+)CD25(high)CD127(low/-) T(reg) cells in AS patients was found to be significantly lower than in healthy controls and was inversely correlated with serum IgA levels. There was no significant correlation between CD4(+)CD25(high)CD127(low/-) T(reg) cell numbers and BASDAI scores. It is concluded that CD4(+)CD25(high)CD127(low/-) T(reg) cells may play a role in the pathogenesis and activity of AS.

Effect of manganese doping on the size effect of lead zirconate titanate thin films and the extrinsic nature of 'dead layers'.

We have investigated the size effect in lead zirconate titanate (PZT) thin films with a range of manganese (Mn) doping concentrations. We found that the dynamic size effect in the conventional Pt/PZT/Pt thin-film capacitors could be systematically reduced and almost completely eliminated by increasing Mn doping concentration. The interfacial layer at the electrode-film interface appears to disappear almost entirely for the PZT films with ∼ 2% Mn doping levels, confirmed by the fits using the conventional 'in-series capacitor' model. Our work indicates that the dynamic size effect in ferroelectrics is extrinsic in nature, supporting the work by Saad et al. Other implications of our results have also been discussed. By comparing a variety of experimental studies in the literature we propose a scenario that the 'dead layer' between PZT (or barium strontium titanate, BST) and metal electrodes such as Pt and Au might have a defective pyrochlore/fluorite-like structure (possibly with a small portion of ferroelectric perovskite phase). This scenario is then generalized by including the effect of the grain-boundary dead layer on the collapse of the dielectric constant in thinner films.

Local phase decomposition as a cause of polarization fatigue in ferroelectric thin films.

We show that lead zirconate titanate thin films undergo local phase decomposition during fatigue. The original remanent polarization of the fatigued film is completely restored after furnace annealing in an O2 atmosphere, following a significant regrowth of a perovskite phase from the pyrochlorelike structure. By comparing our data with other researchers' work on annealing of fatigued ferroelectric samples, we conclude that local phase separation is the generic reason for electrical fatigue in ferroelectrics. A fatigue model is proposed in order to interpret our experimental data.

Extracellular-matrix molecules expressed by innervatable muscle.

Embryonic and adult muscle express distinct complements of proteins. Transplant experiments have shown that embryonic and denervated muscles can form synapses with foreign neurites, while normal innervated mature muscles cannot, except at the synaptic area. To identify molecular differences between 'innervatable' embryonic muscle and 'non-innervatable' mature muscle, we used a differential immunization method to make monoclonal antibodies that recognize antigens present in embryonic muscle rather than normal mature muscle. Four independent monoclonal antibodies that stain embryonic and mature muscle sections differentially have been obtained. One stains the entire embryonic muscle cell surface but only the synaptic area in mature muscle; 3 stain the entire embryonic muscle cell surface but do not stain mature muscle. The antibodies also stain other embryonic tissues at several stages. The antigens are concentrated in basal laminae and in an extracellular-matrix (ECM) fraction, indicating that they are ECM molecules. The temporal expression of all 4 antigens in developing muscle is coincident with muscle innervation. All antigens exhibit temporal and tissue distributions different from those of any reported muscle proteins, suggesting that novel antigens underlie these patterns. These results confirm that the immature muscle ECM has a distinct molecular composition, and suggest that the presence of these antigens may be part of the molecular basis for the innervatability of embryonic muscle.

Patterns of presynaptic gene expression define two stages of synaptic differentiation.

To elucidate the sequence of molecular events leading to nerve terminal differentiation, we have examined the regulation of expression of presynaptic protein genes during synapse formation in vivo. In the chick ciliary ganglion (CG), synaptophysin IIa and synaptophysin IIb mRNAs showed threefold increases relative to neurofilament-M mRNA during the time of target contact [Embryonic Day 7 (E7)-E9]. Expression of synaptotagmin I mRNA also increased severalfold over this time interval. Thus, mRNAs for three synaptic vesicle proteins are upregulated coordinately during synaptogenesis. In contrast, the major increase in choline acetyltransferase (ChAT) mRNA (four- to fivefold) occurred between E15 and E20, coincident with the maturation of synapses in the CG. Coincident with ChAT upregulation, there is a switch in the relative abundance of mRNAs encoding vesicle protein isoforms. In particular, mRNAs encoding synaptophysin IIb and synaptotagmin II (which is undetectable at E9) become predominant. Therefore, although synaptic vesicle protein mRNAs are upregulated in a first phase of differentiation at the time of synapse formation, a temporally distinct phase of presynaptic protein gene regulation, associated with the specific maturation of synapses, is also apparent.

Despite its homology to angiostatin apolipoprotein(a) does not affect angiogenesis.

Apolipoprotein(a) [apo(a)] contains a kringle domain(IV) homologous to that of angiostatin, a natural angiogenic inhibitor. Because of this structural similarity we suspected that apo(a) could be an inhibitor of angiogenesis. The possible role of apo(a) in microvascular proliferation was studied in an in vivo quantitative model, the disc angiogenesis system (DAS) and compared to angiostatin. Apo(a) and other test compounds were placed in the center of a polyvinyl alcohol foam disc that was implanted subcutaneously in mice. After 14 days, the disc was removed and vascular growth into the disc was measured. Apo(a) did not affect spontaneous vessel growth into the disc, while angiostatin suppressed this growth and basic fibroblast growth factor (bFGF) increased it. Additionally, apo(a) did not modify the vascular growth induced by bFGF. Transgenic mice expressing the human apo(a) gene were used to study the systemic effect of apo(a): neither an increase nor a decrease in vascular growth was detected. Our results suggest that apo(a) is unlikely to play a significant role in the control of angiogenesis. Furthermore, our experiments confirm the inhibitory effect of angiostatin not only on induced angiogenesis but also on baseline, spontaneous angiogenesis.

Fibrinogen deficiency reduces vascular accumulation of apolipoprotein(a) and development of atherosclerosis in apolipoprotein(a) transgenic mice.

To test directly whether fibrin(ogen) is a key binding site for apolipoprotein(a) [apo(a)] in vessel walls, apo(a) transgenic mice and fibrinogen knockout mice were crossed to generate fibrin(ogen)-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrin(ogen) deposition was found to be essentially colocalized with focal apo(a) deposition and fatty-streak type atherosclerotic lesions. Fibrinogen deficiency in apo(a) transgenic mice decreased the average accumulation of apo(a) in vessel walls by 78% and the average lesion (fatty streak type) development by 81%. Fibrinogen deficiency in wild-type mice did not significantly reduce lesion development. Our results suggest that fibrin(ogen) provides one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis.