Ascorbic acid and cholesterol: Effect of graded oral intakes on cholesterol conversion to bile acids in guinea-pigs

Summary A significant correlation between liver ascorbic acid (AA) and total bile acids or liver bile acids has been established in guinea-pigs by direct determination of the bile acids, confirming an earlier hypothesis. The oxidation of cholesterol to bile acids is dependent on the AA status, but it cannot be further stimulated by AA when the animals are already on an adequate intake of the vitamin. This suggests that AA has a hypocholesterolaemic effect over a limited range of AA status.     

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.     

Affinity chromatography of soluble galactosyltransferases using an easily synthesized N-acetylglucosamine-agarose bead

Summary Agarose derivatized withp-nitrophenyl-N-acetyl--d-glucosamine was used for affinity chromatography for soluble galactosyltransferase from various sources. Moreover, this adsorbant acts as an acceptor for galactose when incubated with prepurified galactosyltransferase.This work was supported by a grant from the USPHS (grant No. 1 PO1 CA 14294-2).     

Zwei neuartige Erkrankungen bei Insekten

Ohne Zusammenfassung     

Decrease of norepinephrine in brain and heart of vitamin E deficient rats

Zusammenfassung Viermonatiger Vitamin-E-Mangel bewirkt bei Ratten einen etwa 25 prozentigen Abfall des Noradrenalin-Gehaltes in Gehirn und Herz, der durchdl--Tokopherol rückgängig gemacht wird. Die Abnahme des Noradrenalins erfolgt ohne gleichzeitige Verminderung der Tyrosin-Hydroxylase- und Dopamin--Hydroxylase-Aktivität.