Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis

Glatiramer acetate (GA) therapy of patients with multiple sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T cells is consistently observed and associated with clinical benefit in a human autoimmune disease. We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 cytokine network of monocytes in vivo. We further show that Th1- or Th2-polarized GA-reactive T cells isolated from untreated or treated MS patients mediate type 1 and 2 APC differentiation of human monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T cells, respectively. These observations are extended to human microglia, providing the first demonstration of type 2 differentiation of CNS-derived APCs. Finally, we confirm that the fundamental capacity of polarized T cells to reciprocally modulate APC function is not restricted to GA-reactive T cells, thereby defining a novel and dynamic positive feedback loop between human T cell and APC responses. In the context of MS, we propose that GA therapy results in the generation of type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients. In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic immune modulation.     

Complete tumour regressions induced by vaccination with IL-12 gene-transduced tumour cells in combination with IL-15 in a melanoma model in mice

In the present study, IL-12 gene-transduced B78-H1 melanoma cells (B78/IL-12) were used in combination with IL-15 to treat melanoma-bearing mice. Genetically modified B78/IL-12 cells, when injected subcutaneously, induced strong activation of antitumour mechanisms resulting in complete loss of tumourigenicity. In a therapeutic model, intratumoural injection of irradiated B78/IL-12 cells significantly delayed tumour growth and led to the regression of melanoma in one case. Similarly, consecutive daily injections of IL-15 markedly inhibited tumour progression with occasional curative effects. When used in combination, vaccination with B78/IL-12 cells and treatment with IL-15 caused eradication of established tumours in all treated mice. The combined treatment with B78/IL-12 cells and IL-15 activated not only a local response against tumour, but also induced systemic antitumour immunity that led to a delay or inhibition of tumour development at a distant site. In vitro studies demonstrated that when used together, B78/IL-12 cells and IL-15 induced a shift from a type Th2 to a type Th1 response. Activation of the antitumour immune response in double-treated mice resulted, in part, from stimulation of IFN- production and was accompanied by the development of cytotoxic effectors in the spleen. As shown in a macrophage tumouricidal assay, macrophages could also play a role in the antitumour effects. The results confirmed that vaccination with IL-12 gene-modified tumour cells is superior to the treatment with unmodified tumour cell vaccine and, additionally, showed that IL-15 is an excellent candidate for adjuvant therapy, inducing synergistically not only a delay of tumour growth but also its complete eradication.     

Increased local vascular endothelial growth factor expression associated with antitumor activity of proteasome inhibitor

Inhibition of the proteasome, a multicatalytic proteinase complex, is an attractive approach to cancer therapy. Here we report that a selective inhibitor of the chymotrypsin-like activity of the proteasome, PSI (N-benzyloxycarbonyl-Ile-Glu(O-t-butyl)-Ala-leucinal) may inhibit growth of solid tumors not only through apoptosis induction, but also indirectly--through inhibition of angiogenesis. Two murine tumors: colon adenocarcinoma (C-26) and Lewis lung carcinoma (3LL) were chosen to study the antitumor effect of PSI. In an in vivo model of local tumor growth, PSI exerted significant antitumor effects against C-26 colon carcinoma, but not against 3LL lung carcinoma. Retardation of tumor growth was observed in mice treated with both 10 nmoles and 100 nmoles doses of PSI and in the latter group prolongation of the survival time of tumor-bearing mice was observed. PSI inhibited angiogenesis in the C-26 growing tumors with no such effect in 3LL tumors. Unexpectedly, that activity was associated with upregulation of vascular endothelial growth factor (VEGF) at the level of mRNA expression and protein production in C-26 tumors treated with PSI. C-26 cells treated with PSI produced increased amounts of VEGF in vitro in a dose- and time-dependent manner. We demonstrated that in C-26 colon adenocarcionoma higher VEGF production may render endothelial cells susceptible to the proapoptotic activity of PSI and is associated with inhibition of tumor growth.     

The plant traits that drive ecosystems: Evidence from three continents

Question: A set of easily‐measured (‘soft’) plant traits has been identified as potentially useful predictors of ecosystem functioning in previous studies. Here we aimed to discover whether the screening techniques remain operational in widely contrasted circumstances, to test for the existence of axes of variation in the particular sets of traits, and to test for their links with ‘harder’ traits of proven importance to ecosystem functioning. Location: central‐western Argentina, central England, northern upland Iran, and north‐eastern Spain. Recurrent patterns of ecological specialization: Through ordination of a matrix of 640 vascular plant taxa by 12 standardized traits, we detected similar patterns of specialization in the four floras. The first PCA axis was identified as an axis of resource capture, usage and release. PCA axis 2 appeared to be a size‐related axis. Individual PCA for each country showed that the same traits remained valuable as predictors of resource capture and utilization in all of them, despite their major differences in climate, biogeography and land‐use. The results were not significantly driven by particular taxa: the main traits determining PCA axis 1 were very similar in eudicotyledons and monocotyledons and Asteraceae, Fabaceae and Poaceae. Links between recurrent suites of ‘soft’ traits and ‘hard’ traits: The validity of PCA axis 1 as a key predictor of resource capture and utilization was tested by comparisons between this axis and values of more rigorously established predictors (‘hard’ traits) for the floras of Argentina and England. PCA axis 1 was correlated with variation in relative growth rate, leaf nitrogen content, and litter decomposition rate. It also coincided with palatability to model generalist herbivores. Therefore, location on PCA axis 1 can be linked to major ecosystem processes in those habitats where the plants are dominant. Conclusion: We confirm the existence at the global scale of a major axis of evolutionary specialization, previously recognised in several local floras. This axis reflects a fundamental trade‐off between rapid acquisition of resources and conservation of resources within well‐protected tissues. These major trends of specialization were maintained across different environmental situations (including differences in the proximate causes of low productivity, i.e. drought or mineral nutrient deficiency). The trends were also consistent across floras and major phylogenetic groups, and were linked with traits directly relevant to ecosystem processes.     

The antiproliferative effects of cold atmospheric plasma-activated media on different cancer cell lines,the implication of ozone as a possible underlying mechanism

Recent studies have proven several promising anticancer activities for cold atmospheric plasma (CAP) against a wide range of cancer cells in vitro. Recently, media treated with CAP have also found to effectively eradicate cancer cells similar to the CAP. Based on advantages, many researchers prefer to apply CAP-activated media (PAM) as an alternative to cap in the treatment of cancer. However, less has been achieved regarding the anticancer effects and anticancer mechanisms of PAM. Investigating the selective anticancerous activities of PAM, the viability of SKBR3, MCF7, ASPC-1, A-549, G-292, and SW742 cancer cell lines, as well as normal human skin fibroblasts (FMGB-1) and MCF10A cells in relation to the media activation time, and the length of exposure was studied. Also, we examined the concentration of ozone in media as a function to CAP activation time since recent studies have proposed ozone as a pivotal reactive species in the induction of cell death. Based on the result, both increasing the duration of media activation time and the length of exposure to PAM could significantly increase the anticancer activity. Nevertheless, the cytotoxicity on normal cells was either not affected or slightly increased. Among the six tested cancer cell lines, SW742 was the most resistant and SKBR3 the most susceptible cancer cell lines to PAM. Also, increasing duration of treatment with CAP resulted in a significant rise in O₃ concentration levels in media. Overall, these results suggest PAM, as a promising tool in the treatment of different cancers and O ₃ formation as a probable underlying mechanism.     

Predictors of inferior outcome in community acquired bacterial meningitis

The aim of this study was to assess mortality and sequellae within cases from Nationwide survey of community acquired meningitis and identify risk factors for inferior outcome. Risk factors such as underlying disease (diabetes mellitus, cancer, trauma, neonatal age, splenectomy, alcoholism, sepsis, other infections), etiology, clinical symptoms and outcome (death, improvement and cured after modifications of ATB therapy, cured without change of therapy, cured with neurologic sequellae) were recorded and analysed with univariate analysis (chi2 or t test for trends, CDC Atlanta 2004). Analysing risk factors for inferior outcome (death or cured with neurologic sequellae), we compared patients who died or survived with neurologic sequellae to all patients with community acquired bacterial meningitis. Univariate analysis showed that trauma (p<0.05), alcohol abuse (p<0.05), diabetes, S. aureus (p<0.05) and gram-negative etiology (A. baumannii, Ps. aeruginosa or Enterobacteriaceae) (36% vs. 11,9%, p<0.05) were predicting inferior outcome. Analysing risk factors for treatment failure (death or failed but cured after change of antibiotic treatment) prior sepsis (34.1% vs. 13.9%, p<0.01) and gram-negative etiology (25% vs. 11.9%, p<0.02) were statistically significant predictors of treatment failure. Neisseria meningitis had less failures (p<0.05). Concerning infection associated mortality again diabetes mellitus (p<0.05), alcoholism (p<0.05) staphylococcal and gram-negative etiology (p<0.05) were significant predictors of death. N. meningitis had surprisingly less treatment failures (appropriate and rapid initial therapy). Neurologic sequellae were more common in patients with alcohol abuse (p<0.05), craniocerbral trauma (p<0.05) and less common in meningitis with pneumococcal etiology (p<0.05).     

Diet texture modifies outcome of a primary infection with Heligmosomoides polygyrus (nematoda) in mice.

To determine if dietary texture altered the establishment, survival and reproduction of Heligmosomoides polygyrus during a primary infection, commercial mouse chow (Purina Chow) was fed in either pelleted or powdered form to 2 groups of infected BALB/c mice, and a semipurified, biotin-fortified, egg-white-based diet was provided in powdered form to a third group of mice. Diet texture (powdered vs. pelleted) modified parasite establishment, as evidenced by higher worm recovery 6 days postinfection (PI) in both groups of mice fed powdered diets compared with the group fed the pelleted diet, but diet texture had no detectable effect on net or per capita egg production or on day 30 worm survival. However, almost twice as many worms were recovered from mice fed the semipurified, powdered diet than those fed either textural formulation of the commercial mouse chow on day 30 PI, indicating that a dietary component in the semipurified diet, such as the single fiber source cellulose, facilitated parasite survival, or that other ingredients in the commercial mouse chow, perhaps the more complex fiber components, reduced worm survival, or both. We conclude that dietary texture influences parasite establishment and that specific fibers that change texture can individually and independently modify H. polygyrus survival.