25 research outputs found
Palaeo-ecological and archaeological analysis of two Dutch Celtic fields (Zeijen-Noordse Veld and Wekerom-Lunteren): solving the puzzle of local Celtic field bank formation
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.
Space as a Tool for Astrobiology: Review and Recommendations for Experimentations in Earth Orbit and Beyond
Silencing of human ferrochelatase causes abundant protoporphyrin-IX accumulation in colon cancer
Hemes and heme proteins are vital components of essentially every cell of virtually every eukaryote organism. Previously, we demonstrated accumulation of the heme precursor protoporphyrin-IX (PpIX) in gastrointestinal tumor tissues. To elucidate the mechanisms of PpIX accumulation by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we studied expression of the relevant enzymes of the heme synthetic pathway. Here, we describe a significant down-regulation of ferrochelatase (FECH) mRNA expression in gastric, colonic, and rectal carcinomas. Accordingly, in an in vitro model of several carcinoma cell lines, ferrochelatase down-regulation and loss of enzymatic activity corresponded with an enhanced PpIX-dependent fluorescence. Direct detection of PpIX in minute amounts was achieved by a specifically developed pulsed solid-state laser dual delay fluorimetry setup. Silencing of FECH using small interfering RNA (siRNA) technology led to a maximum 50-fold increased PpIX accumulation, imageable by a specifically adapted two-photon microscopy unit. Our results show that in malignant tissue a transcriptional down-regulation of FECH occurs, which causes endogenous PpIX accumulation. Furthermore, accumulation of intracellular PpIX because of FECH siRNA silencing provides a small-molecule-based approach to molecular imaging and molecular therapyKemmner, W., Wan, K., Ruettinger, S., Ebert, B., Macdonald, R., Klamm, U., Moesta, K. T. Silencing of human ferrochelatase causes abundant protoporphyrin-IX accumulation in colon cancer
Molecular imaging of breast cancer in a transgene mouse model [Molekulare Bildgebung des Mammakarzinoms in einem transgenen Mausmodell]
Background: Purpose of the study was to detect early breast cancer and its precursors by in vivo optical molecular imaging in an animal model. Material and methods: Females of the transgene mouse strain WAP-TNP8 develop non-invasive and consequently invasive tumours of the mammary glands due to specific expression of the viral SV40 large tumour antigen induced by lactation. The molecular target for imaging was extradomain-b fibronectin (EDB-FN), which is associated with tumour angiogenesis. The optical probe was designed as a compound of an anti-EDB-FN antibody fragment and a near-infrared fluorescent dye. 30h after intravenous injection of the contrast agent, optical imaging was performed using a pulsed Laser system for excitation and an intensified CCD-camera to record fluorescence images. After optical molecular imaging all animals were sacrified and the tumours were examined histologically. Results: Initiated transgene female animals developed palpable masses of the mammary gland within 6 months (median 4 months). Imaging was performed in 5 animals with a total of 9 tumours (diameter 2–7mm, median 4mm). Applying optical molecular imaging 8 of 9 tumours were detected. The urogenital tract was contrasted unspecifically. Histological examination proved invasive epithelial tumours of the mammary gland in all cases. Conclusion: Breast cancer can be detected in vivo by near-infrared fluorescence molecular imaging targeting neoangiogenesis in a transgene mouse-model