A p-menthane derivative isolated from culture filtrates ofFusicoccum amygdali,Del.

Summary From culture filtrates ofFusicoccum amygdali, Del., a new compound, whose structure corresponds to 1,2,3-trihydroxy-p-menthane, has been isolated. Its discovery is of some interest since, to our knowledge, it is the first time that a monoterpenoid is isolated from a microorganism.     

Concentration of "available" unesterified cholesterol in human plasma as evaluated from inhibition of hemolysis by lucensomycin.

The unesterified cholesterol content of plasma samples can be evaluated from the extent of inhibition of lucensomycin-induced hemolysis. The test measures, however, only the fraction of cholesterol which is available for interaction with lucensomycin, this availability being adversely affected by high phospholipid-cholesterol ratios.     

Characterization of by-products of fusicoccin in culture filtrates ofFusicoccum amygdali Del

Riassunto Dai brodi di coltura diFusicoccum amygdali Del. sono stati isolati un isomero della fusicoccina (isofusicoccina), una monodeacetilfusicoccina, in cui manca 1'acetile sul residuo del glucosio, e la dideacetilfusicoccina.

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On leave from the Instituto di Chimica Farmaceutica e Tossico logica dell'Università di Perugia.     

Ein chemisch und pharmakologisch neuartiger Antagonist von pathophysiologisch bedeutsamen Aminen,Kininen und kininbildenden Faktoren

Summary CIBA 21 401-Ba, a glucofuranoside derivative (ethyl-3,5,6-O-benzyl-d-glucofuranoside), antagonizes in vitro the smooth-muscle action of a large number of biogenic amines and polypeptides, the accelerated migration of leucocytes induced by endotoxin, and the Schultz-Dale phenomenon. In vivo, the compound shows anti-inflammatory and anti-allergic effects and improves the survival rate of infected mice treated with suboptimal doses of a sulphonamide.     

Activation of fatty acids in the liver in carbon tetrachloride poisoning

Zusammenfassung Bei CCl₄-Vergiftung zeigt die Leber eine vermehrte Aktivierung der Fettsäuren, die sich fast gleichzeitig mit der fettigen Infiltration kundgibt. Die Abnahme der Aktivierung äussert sich bereits 5 h nach der Vergiftung in statistisch signifikanter Weise. Zugabe von CCl₄ hemmtin vitro die Aktivierung von Palmitin- und Buttersäure.     

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.