Abnahme und Ablieferung von DV-Anlagen

Im Anschluss an den Beitrag über die Abnahme technischer Anlagen in CR 1991, 1-6 soll eine Auswahl der Rechtsprechung zur Abnahme und Ablieferung von DV-Anlagen untersucht werden. Dabei wird die Tendenz erkennbar, den Zeitpunkt der Abnehme gem. § 640 BGB als Auslöser der Zahlungspflicht und Verjährungsbeginn der Gewährleistungsrechte möglichst weit hinauszuschieben. Bedenklich erscheint diese Ausdehnung des Schutzes dort, wo die für die werkvertragliche Abnahme entwickelten Kriterien auf die kaufrechtliche Ablieferung übertragen werden, auf die sie wegen der andersartigen Ausgestaltung des Kaufvertrages jedoch nicht passen. Auch bei der vertraglichen Ausgestaltung des Abnahmeverfahrens ist auf §§ 10 Nr. 1 und 5 AGBG und die hierzu von der Rechtsprechung entwickelten Grundsätze Rücksicht zu nehmen, wie anhand einer Auswahl von Vertragsmustern gezeigt werden soll

ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids

Chemotherapy resistance is a major challenge in ovarian cancer (OvCa). Thus, novel treatment combinations are highly warranted. However, many promising drug candidates tested in two-dimensional (2D) cell culture have not proved successful in the clinic. For this reason, we analyzed our drug combination not only in monolayers but also in three-dimensional (3D) tumor spheroids. One potential therapeutic target for OvCa is A disintegrin and metalloprotease 17 (ADAM17). ADAM17 can be activated by chemotherapeutics, which leads to enhanced tumor growth due to concomitant substrate cleavage. Therefore, blocking ADAM17 during chemotherapy may overcome resistance. Here, we tested the effect of the ADAM17 inhibitor GW280264X in combination with cisplatin on ovarian cancer cells in 2D and 3D. In 2D, the effect on five cell lines was analyzed with two readouts. Three of these cell lines formed dense aggregates or spheroids (HEY, SKOV-3, and OVCAR-8) in 3D and the treatment effect was analyzed with a multicontent readout (cytotoxicity, viability, and caspase3/7 activation). We tested the combined therapy on tumor spheroids derived from primary patient cells. In 2D, we found a significant reduction in the half minimal (50%) inhibitory concentration (IC50) value of the combined treatment (GW280264X plus cisplatin) in comparison with cisplatin monotherapy in all five cell lines with both 2D readout assays (viability and caspase activation). In contrast, the combined treatment only showed an IC50 reduction in HEY and OVCAR-8 3D tumor spheroid models using caspase3/7 activity or CelltoxTM Green as the readout. Finally, we found an improved effect of GW280264X with cisplatin in tumor spheroids derived from patient samples. In summary, we demonstrate that ADAM17 inhibition is a promising treatment strategy in ovarian cancer

Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein

OBJECTIVE: Apolipoprotein M (ApoM) enriches sphingosine-1-phosphate (S1P) within high density lipoproteins (HDL) and facilitates the activation of the S1P(1) receptor by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question how S1P regulates transendothelial HDL transport. APPROACH AND RESULTS: HDL were isolated from plasma of wild type mice, Apom knock-out mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells (BAECs and HAECs, respectively). We also compared the transport of fluorescently-labeled HDL or Evan’s Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (S1P(1)-iECKI) or without (CTRL) endothelium specific knock-in of S1P(1). The binding, association, and transport of HDL from Apom knock-out mice and human apoM-depleted HDL by BAECs was significantly lower than that of HDL from wild type mice and human apoM containing HDL, respectively. The binding, uptake, and transport of (125)I-HDL by HAECs was increased by an S1P(1) agonist but decreased by an S1P(1) inhibitor. Silencing of scavenger receptor BI (SR-BI) abrogated the stimulation of (125)I-HDL transport by the S1P(1) agonist. Compared to CTRL, S1P(1)-iECKI showed decreased transport of Evan’s Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. CONCLUSIONS: ApoM and S1P(1) promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration

Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein

Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration. Keywords: apolipoprotein; endothelium; lipoprotein; mice; sphingosine-1-phosphate