268 research outputs found
Patente als Sicherheiten bei der Kreditvergabe
Im November letzten Jahres veranstaltete das Europäische Patentamt einen Workshop zu den Veränderungen, die sich aus der Einführung von Vorschlägen zur Neufassung der Baseler Eigenkapitalvereinbarung von 1988 ergeben, die darauf zielen, die Kapitalanforderungen an Banken stärker als bisher vom ökonomischen Risiko abhängig zu machen. Diese Neuregelung sieht bei der Bestimmung der Eigenkapitalquote eine Reihe von Ansätzen zur Messung des Kreditrisikos und des operationellen Risikos vor und eröffnet gleichzeitig die Möglichkeit der Einbeziehung weiterer, bisher nicht berücksichtigter Sicherheiten, zu denen auch Patente gehören können, sofern ihre wirtschaftliche Bedeutung belegt werden kann. Dies bietet technologieorientierten, kleineren Firmen Möglichkeiten, ihre Kreditbedingungen zu verbessern. In zwei hier dokumentierten Vorträgen stellen Guido von Scheffer und Dirk Loop, IP Bewertungs AG, Hamburg, und Dr. Holger Himmel und Sven Mussler, PricewaterhouseCoopers, Frankfurt am Main, verschiedene Alternativen der Patentbewertung zur Absicherung von Kreditrisiken vor.Patent, Kreditgeschäft, Eigenkapital, Kreditrisiko, Finanzierung, Bewertung, Immaterielles Anlagevermögen
Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport
AbstractWe studied the ATP-dependent uptake of dinitrophenyl-glutathione (GS-DNP) into plasma membrane vesicles derived from parental GLC4 cells and from multidrug resistant GLC4/ADR cells. The latter have a high expression of the multidrug resistance protein (MRP). Uptake of GS-DNP into membrane vesicles from GLC4/ADR cells was highly stimulated by the addition of ATP, compared to the uptake into membrane vesicles from GLC4 cells. This ATP-dependent uptake into membrane vesicles from GLC4/ADR cells was saturable with a Km of 1.2±0.2 μM and a Vmax of 560±80 pmol/mg prot./min. ATP stimulated GS-DNP uptake with a Km of 187±4 μM. This uptake was specifically inhibited by a polyclonal serum raised against a fusion protein containing a segment of MRP. The ATP-dependent uptake of GS-DNP was not only inhibited by organic anions, such as oxidized glutathione (GSSG), methotrexate (MTX) and some bile acids, but also by non-anionic natural product drugs, such as anthracyclines, vinca alkaloids and etoposide (VP-16). Uptake of GSSG and MTX into membrane vesicles from GLC4/ADR cells could be stimulated by ATP. The ATP-dependent uptake of GSSG had a Km of 43±3 μM and a Vmax of 900±200 nmol/mg protein/min. The ATP-dependent uptake of GS-DNP seemed to be non-competitively inhibited by the anthracycline daunorubicin (DNR), whereas the ATP-dependent GSSG uptake seemed to be competitively inhibited by DNR. A substrate binding site on MRP is proposed that comprises a pocket in which both DNR and GS-DNP or GSSG bind in random order to different, only partly overlapping sites. In this pocket binding of a second compound is influenced by the compound which was bound first
Molecular determinants of treatment response in human germ cell tumors
PURPOSE: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based
chemotherapy. This feature is unexplained, as is the intrinsic
chemotherapy resistance of mature teratomas and the resistant phenotype of
a minority of refractory GCTs. Various cellular pathways may influence the
efficacy of chemotherapy. Their impact has not been investigated in a
comprehensive study of tumor samples from clinically defined subgroups of
GCT patients. EXPERIMENTAL DESIGN: We investigated proteins involved in
regulation of apoptosis (p53, BAX, BCL-2, and BCL-X(L)), cell cycle
control [p21 and retinoblastoma protein (RB)], and drug export and
inactivation [P-glycoprotein, multidrug resistance-associated protein
(MRP) 1, MRP2, breast cancer resistance protein, lung resistance protein,
metallothionein, and glutathione S-transferase pi] immunohistochemically
in samples of unselected GCT patients (n = 20), patients with advanced
metastatic disease in continuous remission after first-line chemotherapy
(n = 12), and chemotherapy-refractory patients (n = 24). Mature teratoma
components (n = 10) within tumor samples from all groups were analyzed
separately. The apoptotic index was studied by terminal deoxynucleotidyl
transferase-mediated nick end labeling assay. RESULTS: Invasive GCTs of
all groups showed a correlation between wild-type p53 and apoptotic index
(r(s) = 0.66; P < 0.001). The levels of the antiapoptotic proteins BCL-2
and BCL-X(L) were generally low. p21 was hardly detectable and did not
correlate with p53 (r(s) = 0.29; P = 0.07). No significant differences
among the three patient groups were identified regarding any of the
investigated parameters (all Ps were >0.08), even though only individual
samples from chemotherapy-resistant cases showed a strong staining for
MRP2 and GSTpi. In contrast to other components, mature teratomas showed
an intense p21 and RB staining and were mostly positive for MRP2, lung
resistance protein, and GSTpi. CONCLUSIONS: Our results indicate a
multifactorial basis for the chemosensitivity of GCTs with lack of
transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21
induction by p53, and of RB and an intact apoptotic cascade downstream of
p53. These findings suggest a preference for apoptosis over cell cycle
arrest after up-regulation of p53. None of the examined parameters offers
a general explanation for the chemotherapy-resistant phenotype of
refractory tumors. The up-regulation of various factors interfering with
chemotherapy efficacy and ability for a p21-induced cell cycle arrest may
explain the intrinsic chemotherapy resistance of mature teratomas
Recommended from our members
Reply to Bhowmik et al.: Democratic climate action and studying extreme climate risks are not in tension
[no abstract available
Recommended from our members
Reply to Kelman: The foundations for studying catastrophic climate risks
Recommended from our members
Reply to Ruhl and Craig: Assessing and governing extreme climate risks needs to be legitimate and democratic
[No abstract available
Recommended from our members
Reply to Burgess et al: Catastrophic climate risks are neglected, plausible, and safe to study
Natural Exon Skipping Sets the Stage for Exon Skipping as Therapy for Dystrophic Epidermolysis Bullosa
Contains fulltext :
214010.pdf (publisher's version ) (Open Access
Mechanisms of Natural Gene Therapy in Dystrophic Epidermolysis Bullosa
Item does not contain fulltextRevertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies
- …