Die subjektive Seite oekonomischen Verhaltens Theoretische Ueberlegungen, empirische Ergebnisse, politische Perspektiven. Stand: Juni 1984

Bibliothek Weltwirtschaft Kiel Q3822 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Flavonoids alter P-gp expression in intestinal epithelial cells in vitro and in vivo.

Flavonoids are secondary plant metabolites included in our diet but are also provided in a growing number of supplements. They are suggested to interact with intestinal transport systems including phospho-glycoprotein (P-gp) which mediates the efflux of a variety of xenobiotics back into the gut lumen. In human intestinal Caco-2 cells, we tested the effects of 14 different flavonoids on P-gp expression in vitro. Protein expression levels were quantified by Western blotting, flow cytometry, and real-time PCR. Except apigenin, all flavonoids at concentrations of 10 M increased P-gp expression in Western blotting experiments when cells were exposed to the compounds over 4 wk. Flavone was one of the most effective P-gp inducers in Caco-2 cells and its effects were, therefore, also assessed for changes in P-gp in vivo in the gastrointestinal tract of C57BL/6 mice. P-gp expression was significantly increased by flavone (400 mg/kg body weight×day over 4 wk) in the small intestine but not in the colon which displayed intrinsically the highest expression level. In conclusion, the increase in P-gp expression caused by flavonoids in intestinal epithelial cells in vitro and also in vivo may serve as an adaptation and defense mechanism limiting the entry of lipophilic xenobiotics into the organism

Improved detection of minimal residual disease by flow cytometry in AML by combining manual gating and visne clustering.

Background: In acute myeloid leukemia (AML), detection of minimal residual disease (MRD) by flow cytometry is an adverse prognostic factor besides pre-treatment risk classifications, including cytogenetic and molecular aberrations. High dimensional multiparameter flow cytometry (MPFC) offers improved sensitivity and specificity, however manual analysis is increasingly challenging. In this study, we explore the value of the recently proposed viSNE algorithm to quantify MRD levels in patients with AML achieving complete remission (CR) after intensive induction chemotherapy. Methods: Bone marrow samples from patients with AML (excluding patients with acute promyelocytic leukemia) were analyzed by 8-10 MPFC using a NAVIOS flow cytometer (Beckman Coulter, Brea, CA, USA). Only patients achieving a CR or CR with incomplete blood count recovery (CRi) post-induction were included in this analysis. Manual gating of MRD flow data was performed as described previously (Köhnke et al., Leukemia 2014) using a cutoff for MRD positivity of 0.1%. The viSNE algorithm was performed as described previously (Amir et al., Nat. Biotech. 2013) and MRD positivity was defined as the presence of a distinct cluster of >100 cells which consisted of >90% patient cells. Kaplan-Meier estimator and log-rank test as well as Cox's proportional hazards regression model were used to analyze survival data. Results: Post-induction flow cytometry and clinical data of 38 patients with AML achieving CR (n=34) or CRi (n=4) were available for analysis (median age 53 years; de-novo AML n=32, tAML n=1, sAML n=5). Most patients belonged to the intermediate cytogenetic risk group (MRC favorable n=5, intermediate n=22, adverse n=11). 19/38 patients were MRD positive post-induction by manual gating. 12/19 patients deemed MRD positive relapsed, whereas 3/19 patients deemed MRD negative relapsed. Therefore, MRD positivity by manual gating correlated with reduced relapse free survival (median RFS for MRD positive patients: 7.5 months vs. median not reached for MRD negative patients, log-rank test p=0.017). For overall survival (OS), no significant impact of MRD positivity could be detected so far (p=0.3), however follow-up was short (median follow-up 9.3 months). MRD positivity by manual gating remained an independent risk factor for RFS (HR 4.8, p=0.021) when compared to genetic risk and age. MRD positivity by viSNE clustering was seen in 19/38 patients. 10/19 patients deemed MRD positive by viSNE relapsed, while 5/19 deemed MRD negative by viSNE experienced a relapse. This resulted in a trend towards shorter RFS for MRD positivity by viSNE (median RFS 9.9 months vs. 19.0 months for MRD negative patients, p=0.185). Among the patients deemed MRD positive by viSNE who did not relapse, i.e. false-positive patients, follow-up was very short (<3.5 months) in 4/9 cases and final judgment whether these patients are truly negative should be withheld. However, differentiation between healthy monocytes and potential MRD cells by viSNE seems to be especially challenging and warrants optimization. Nevertheless, within the group of patients deemed MRD negative by manual gating, viSNE was able to detect all patients who experienced a subsequent relapse. To maximize sensitivity for MRD detection, we therefore combined the results of both methods and defined MRD positivity as positivity by manual gating and/or viSNE clustering. Using this combined strategy, 28/38 patients were defined as MRD positive and 10/38 as MRD negative. Within the MRD positive group, 15/28 patients relapsed, whereas none of the patients in the MRD negative group relapsed (Figure 1, median RFS for MRD positive patients: 7.7 months, log-rank test p=0.028). Of note, within the MRD negative group only 2 patients (both with intermediate genetic risk) went on to receive a allogeneic stem cell transplantation whereas 8 remained in remission with chemotherapy alone. Conclusion: In summary, viSNE clustering used in combination with manual gating improves the sensitivity of MRD detection by flow cytometry. Importantly, viSNE is able to detect MRD positivity within the manual MRD negative patient population. This is the first report of MRD detection in AML using this method. However, improvements in the algorithm as well as further studies are needed to validate the prognostic value of viSNE clustering in AML

Fine particle number and mass concentration measurements in urban Indian households

Fine particle number concentration (Dp>10 nm, cm−3), mass concentrations (approximation of PM2.5, μg m−3) and indoor/outdoor number concentration ratio (I/O) measurements have been conducted for the first time in 11 urban households in India, 2002. The results indicate remarkable high indoor number and mass concentrations and I/O number concentration ratios caused by cooking. Besides cooking stoves that used liquefied petroleum gas (LPG) or kerosene as the main fuel, high indoor concentrations can be explained by poor ventilation systems. Particle number concentrations of more than 300,000 cm−3 and mass concentrations of more than 1000 μg m−3 were detected in some cases. When the number and mass concentrations during cooking times were statistically compared, a correlation coefficient r>0.50 was observed in 63 of the households. Some households used other fuels like wood and dung cakes along with the main fuel, but also other living activities influenced the concentrations. In some areas, outdoor combustion processes had a negative impact on indoor air quality. The maximum concentrations observed in most cases were due to indoor combustion sources. Reduction of exposure risk and health effects caused by poor indoor air in urban Indian households is possible by improving indoor ventilation and reducing penetration of outdoor particles