TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis

Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.     

Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening

In the alternative pathway of telomere lengthening (ALT), neoplastic cell growth is prolonged by telomere recombination. We show that ALT is unexpectedly characterized by high rates of ongoing pericentromeric chromosomal instability. Combined with telomeric recombination, ALT pericentromeric instability generates neoacrocentric chromosomes. In the present studies, we describe a subgroup of ALT neoacrocentric minute chromosomes, composed of DNA entities two to five times smaller in size than human chromosome 21. The frequencies of ALT minute chromosomes were increased by gamma-irradiation and suppressed by telomerase. Continuous growth after telomerase inhibition/depletion was followed by increased rates of telomeric sister chromatid recombination and the emergence of minute chromosomes. We show that ALT minute chromosomes were derived from true centromeric fissions and/or chromosomal breakage/fusion/bridge cycles. They exhibit a two-chromatid structure, carry genomic DNA, centromeric and telomeric repeats, and display regular mitotic functionality. These observations are important in understanding the global genomic instability that characterizes most human advanced malignancies.     

Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate

AIMS: To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. METHODS: Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg ('test') or two tablets of 200 mg ('reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. RESULTS: Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 microg ml(-1) (test), and 18.2 and 20 microg ml(-1) (reference). Areas under the plasma concentration vs. time curves were 39.7 and 67.5 microg ml(-1) h (test), and 41.1 and 68.2 microg ml(-1) h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h(-1) (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h(-1), central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h(-1), peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h(-1), and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. CONCLUSIONS: Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen.     

Humangenetische Beratung in Deutschland: Entwicklung der Inanspruchnahme

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Mit dem Gendiagnostikgesetz (GenDG) hat der deutsche Gesetzgeber tief greifende Vorschriften für die humangenetische...     

Laser acupuncture and probiotics in school age children with asthma: a randomized, placebo-controlled pilot study of therapy guided by principles of Traditional Chinese Medicine

Traditional Chinese Medicine (TCM) postulates an interaction between the lung as a Yin-organ and the large intestine as a Yang-organ. The aim of this pilot study was to investigate in asthmatic school age children whether treatment with laser acupuncture and probiotics according to TCM portends a clinical benefit to standard medical treatment performed according to pediatric guidelines. Seventeen children aged 6-12 yr with intermittent or mild persistent asthma were enrolled in this randomized, placebo-controlled, double-blind pilot study. Eight patients received laser acupuncture for 10 wk and probiotic treatment in the form of oral drops (living non-pathogenic Enterococcus faecalis) for 7 wk. Nine patients in the control group were treated with a laser pen which did not emit laser light and were given placebo drops. Peak flow variability (PFV) and forced expiratory volume in 1 s (FEV(1)) were measured and Quality of Life was assessed by a standardized questionnaire. Laser acupuncture and probiotics significantly decreased mean (standard deviation) weekly PFV as a measurement of bronchial hyperreactivity by -17.4% (14.2) in the TCM group vs. 2.2% (22.5) in the control group (p = 0.034). No significant effect was detected for FEV(1), Quality of Life criteria and additional medication. As an exploratory result, patients in the TCM group had fewer days of acute febrile infections when compared with the control group [1.14 (1.4) vs. 2.66 (2.5), p = 0.18]. In conclusion, this pilot study generates the hypothesis that the interactive treatment of lung and large intestine according to TCM by laser acupuncture and probiotics has a beneficial clinical effect on bronchial hyperreactivity in school age children with intermittent or mild persistent asthma and might be helpful in the prevention of acute respiratory exacerbations. These results should be confirmed by further studies.     

Sexualstörungen bei Diabetes mellitus

In diabetology sexual dysfunction has been for years and still is a neglected area. Diabetologists may fail to recognize that sexual disorders, especially erectile dysfunction, are complications of diabetic metabolism. Thus sexual dysfunction in diabetic patients may be considered to represent only a slight change in lifestyle and not a disease that needs to be treated. A main objective in treating diabetic patients today is to keep their quality of life as high as possible. Sexual dysfunction means a reduction in quality of life. Therefore, if desired, it should be treated. In diabetic patients sexual dysfunction is found more often and at a younger age than in the non-diabetic population. Sexual dysfunction in diabetic women has not been well investigated and treated. Erectile dysfunction is the most important sexual disorder in diabetic men. There are many therapeutic opportunities that work very well in these men. At present many of these men prefer to take PDE-5 inhibitors which is the most comfortable treatment.