Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells

25-Hydroxyvitamin D3-1 alpha-hydroxylase (25(OH)D3-1 alpha-hydroxylase), the key enzyme of 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) production, is expressed in monocyte-derived macrophages (MACs). Here we show for the first time constitutive expression of 25(OH)D3-1 alpha-hydroxylase in monocyte-derived dendritic cells (DCs), which was increased after stimulation with lipopolysaccharide (LPS). Accordingly, DCs showed low constitutive production of 1,25(OH)2D3, but activation by LPS increased 1,25(OH)2D3 synthesis. In addition, 25(OH)D3-1 alpha-hydroxylase expression was found in blood DCs but not in CD34+-derived DCs. Next we analyzed the functional consequences of these results. Addition of 1,25(OH)2D3 at concentrations comparable with those produced by DCs inhibited the allostimulatory potential of DCs during the early phase of DC differentiation. However, terminal differentiation decreased the responsiveness of DCs to 1,25(OH)2D3. In conclusion, DCs are able to produce 1,25(OH)2D3 especially following stimulation with LPS. Terminal maturation renders DCs unresponsive to the effects of 1,25(OH)2D3, but those cells are able to suppress the differentiation of their own precursor cells in a paracrine way through the production of 1,25(OH)2D3.     

Cytotoxic activity in the serum of a patient with metastasizing nephroblastoma given intravenous infusions of alkyl-lysophospholipids in a phase I study

Summary In a phase I study a cytotoxic activity in the serum of a tumor patient given infusions of synthetic alkyl-lysophospholipid has been demonstrated. Serum samples collected after ALP infusions inhibited ³H-thymidine incorporation by human leukemic cells to an extent that correlated to the dose of ALP administered. Serum taken after the highest dose of ALP given (50 mg/kg body weight) led to complete cell destruction after 72 h in vitro. Whereas cells from the HL60 line were very sensitive to the serum cytotoxicity, K562 cells were much less affected. Cytotoxic activity was found to be cleared from the circulation in a biphasic manner; more than 50% disappeared within 6–8 h but 20–30% was still present after 4 days.Supported by DFG An 111/2     

Combination chemotherapy of advanced medullary and differentiated thyroid cancer

Summary A group of 20 patients with advanced medullary (MTC) or differentiated thyroid carcinoma (DTC) received a combination chemotherapy of doxorubicin (50 mg/m²), cisplatin (60 mg/m²) and vindesine (3 mg/m²). In the 18 (10 MTC, 8 DTC) evaluable patients only 1 partial remission (in a patient with MTC) and 3 minor responses (in 3 patients with DTC) were observed. These responses lasted for 15, 9, 13, and 22 months, respectively. Three MTC patients suffered from progressive disease and no change was seen in the other 11 patients. Toxicity, including 1 severe case of cardiomyopathy, was considerable. Thus, the combination chemotherapy of doxorubicin, cisplatin and vindesine has failed to prove superior to the commonly applied doxorubicin monotherapy in patients with advanced medullary or differentiated thyroid carcinoma.Abbreviations MTC, DTC medullary and differentiated thyroid carcinoma This study was supported by a grant of the German Cancer Research Center (Tumorzentrum Heidelberg/Mannheim)     

Variance stabilization for computing and comparing grand mean waveforms in MEG and EEG

Grand means of time‐varying signals (waveforms) across subjects in magnetoencephalography (MEG) and electroencephalography (EEG) are commonly computed as arithmetic averages and compared between conditions, for example, by subtraction. However, the prerequisite for these operations, homogeneity of the variance of the waveforms in time, and for most common parametric statistical tests also between conditions, is rarely met. We suggest that the heteroscedasticity observed instead results because waveforms may differ by factors and additive terms and follow a mixed model. We propose to apply the asinh‐transformation to stabilize the variance in such cases. We demonstrate the homogeneous variance and the normal distributions of data achieved by this transformation using simulated waveforms, and we apply it to real MEG data and show its benefits. The asinh‐transformation is thus an essential and useful processing step prior to computing and comparing grand mean waveforms in MEG and EEG.