Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma

Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.     

Acute effects of alcohol on divided and covert attention in men

RATIONALE: While several studies identified divided attention to be sensitive to alcohol effects, the impact of alcohol on covert visual attention is still not clear, despite the latter's important role in perception. OBJECTIVES: The study tests the effect of acute moderate doses of alcohol on divided and covert attention in right-handed, male volunteers. METHODS: The design of the study involved a double-blind trial with an alcohol and a placebo condition; measurements were taken before and after an oral dose of 0.6 g/kg alcohol versus placebo. In the divided-attention task, simultaneous visuo-spatial and auditory stimulation was applied. In a test of covert attention, subjects had to shift their attentional focus according to a central cue, from one location in the visual field to another. RESULTS: Under the divided-attention condition, reaction times were significantly prolonged after alcohol ingestion compared to placebo. Covert attention pre-post change was also significantly different between the alcohol and placebo groups. There is a reduction of false-cueing disturbance for left-appearing stimuli under moderate alcohol but an increase of disturbance for rightward stimuli, i.e. we found a lateralised pattern of reaction for spatial orienting. In the placebo group, no significant differences in right-left performance were obtained. CONCLUSION: The results suggest that sensory-attentional mechanisms play a key role in altered visual perceptual performance after alcohol ingestion. Furthermore, differences between the right and left visual field in the cued target-detection task indicate that alcohol exerts an influence on right-hemispheric attentional priming.     

Simultaneous in vivo measurements of intranasal air and mucosal temperature

Nasal cavity volume and blood temperature along the nasal airways, reflecting the mucosal temperature, are considered to be the most important predictors of nasal air conditioning. The purpose of this study was to simultaneously in vivo measure intranasal air as well as mucosal temperature for the first time. Fifteen healthy subjects were enrolled into the study. Two combined miniaturized thermocouples were used for simultaneous recording of intranasal air and mucosal temperature within the anterior turbinate area close to the head of the middle turbinate without interruption of nasal breathing. The highest air and mucosal temperature values were detected at the end of expiration, the lowest values at the end of inspiration. The difference was statistically significant (P < 0.05). The mean mucosal temperature ranged from 30.2 ± 0.9 to 32.2 ± 0.8°C. The mean air temperature ranged from 28.5 ± 1.2 to 34.1 ± 0.7°C. The mean differences between air and mucosal temperature were 1.7 ± 0.5°C after inspiration and 1.9 ± 0.7°C after expiration. Simultaneous measurements of intranasal air and mucosal temperature are practicable. The detected temperature gradient between air and mucosa confirm a relevant heat exchange during inspiration and expiration. This gradient between air and mucosa is obligatory for heat and water exchange to ensure adequate nasal air conditioning.     

HCV—specific cytokine induction in monocytes of patients with different oputcomes of hepatitis C

AIM：Cytokine release by macrophages critically determines the type of immune response to an antigen Therefore.we studied hepatitis C virus (HCV0-Specific induction of interleukins-1β,-10,-12(IL-1β,il-10,IL-12),and tumor necrosis factor-α(TNF-α) in monocytes.METHODS:Intracellular cytokine expression was studied by flow cytometry in 23 patients with chronic hepatitis C,14 anti-HCV seropositives without viremia and 11 controls after stimulation of peripheral blood mononuclear cells with recombinant core,NS3,NS4 NS5a and NS5b proteins .RESULTS:Patients with HCV viremia revealed greater spontaneous exprssion of IL-1β,TNF-α,and IL-10,Furthermore,greater than twofold higher IL-10 epression was induced by the HCV antigens in chronic hepatitis C than in the other two groups (P&lt;0.05) In contrast,neither IL-12 noir TNF-α was induced preferentially.CONCLUSION:In chonic hepatitis C antigen-specific cytokine induction in monocytes is apparently shifted towards predominant IL-10 induction-not counterbalanced by antiviral type 1 cytokines,This may contribute to persistent viral replication.     

Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis

Th1 and Th17 subtype effector CD4(+) T cells are thought to play a critical role in the pathogenesis of human and experimental crescentic glomerulonephritis. The time course, mechanism, and functions of Th1 and Th17 cell recruitment, and their potential interaction in glomerulonephritis, however, remain to be elucidated. We performed interventional studies using IL-17- and IFN-γ-gene-deficient mice, as well as neutralizing antibodies that demonstrated the importance of the Th17-mediated immune response during the early phase of the disease. At a later stage, we found that Th1 cells were critical mediators of renal tissue injury. Early recruitment of IL-17-producing Th17 cells triggered expression of the chemokine CXCL9 in the kidney that drove the infiltration of Th1 cells bearing its receptor CXCR3. At a later stage, Th1 cell-derived IFN-γ was found to inhibit local chemokine CCL20 expression, acting through its receptor CCR6 on Th17 cells, thereby limiting the renal Th17 immune response. Thus, our findings provide mechanistic evidence for a cytokine-chemokine-driven feedback loop that orchestrates the observed differential Th1 and Th17 cell infiltration into the inflamed kidney. This contributes to the observed time-dependent function of these two major pathogenic effector CD4(+) T cell subsets in crescentic glomerulonephritis.     

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.     

Reproducibly emitting reference materials for volatile and semi-volatile organic compounds—using finite element modeling for emission predictions

Recent research into emissions of (semi-)volatile organic compounds [(S)VOC] from solid materials has focused on the development of suitable reference materials for quality assurance/quality control of emission test chamber measurements, which fulfill requirements such as homogenous and reproducible (S)VOC release. The approach of this study was to find a method for preparation of a material with predictable (S)VOC emission rates. A VOC (styrene) and an SVOC (2,6-diisopropylnaphthalene, DIPN), loaded into either vacuum grease or a 1:1 mixture of paraffin/squalane, have been tested. For the prediction of the emission rates, a model using the finite element method (FEM) was created to simulate the (S)VOC emission profiles. Theoretical and experimental results obtained in a Micro-Chamber/Thermal Extractor (μ-CTE?) and in 24 L emission test chamber measurements were in good agreement. Further properties were investigated concerning the material applicability, such as shelf life and inter-laboratory comparability. The maximum relative standard deviation in the inter-laboratory study was found to be 20%.     

Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HR_log2?=?1.06, 95% CI 0.99–1.14) or in men (HR_log2?=?0.97, 95% CI 0.90–1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HR_log2?=?0.91, 95% CI 0.85–0.97) and positively associated with rectal cancer in women (HR_log2?=?1.10, 95% CI 1.02–1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.     

Accumulation of polycyclic aromatic hydrocarbons in rural soils based on mass balances at the catchment scale

Polycyclic aromatic hydrocarbons (PAHs) are hydrophobic organic pollutants that are ubiquitously distributed in the environment at relatively high concentrations. In our study we investigated the long-term fate of atmospheric PAHs in soils of rural areas, resulting from diffuse pollution based on mass balances at the catchment scale. By determining PAHs in several environmental compartments, estimates of soil storages and water fluxes were made and compared with atmospheric deposition. The results indicate that more than 90% of the incoming PAHs remain in the catchments and accumulate in the topsoils. Furthermore, revolatilization of PAHs from soils and degradation in the soils is very limited, resulting in ongoing accumulation in topsoils, in particular for low-volatile PAHs. Combustion-derived carbonaceous particles were detected in atmospheric deposition as well as in the soil samples. Since these particles are very strong adsorbents, they are suspected to play a key role in the environmental fate of the diffuse distributed PAHs.