FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.     

Integrating genomics against infectious disease

The most recent National Academies Keck Futures Initiative Conference, entitled 'The Genomics Revolution: Implications for Treatment and Control of Infectious Disease', was held at the Arnold and Mabel Beckman Center in Irvine, California. It provided strategies and opportunities for interdisciplinary collaboration and incentives to innovate.     

Structure of a genomic clone encoding biologically active human relaxin

Relaxin is a peptide hormone synthesized in the corpora lutea of ovaries during pregnancy and is released into the blood stream prior to parturition. Its major biological effect is to remodel the mammalian reproductive tract to facilitate the birth process. Determination of the structure of human relaxin is thus a first step in opening up the possibility of clinical intervention in cases of difficult labour. However, the limited availability of human ovaries during pregnancy has prevented both direct amino acid sequence determination and isolation of cDNA clones obtained from relaxin producing tissue. Our approach has therefore been to screen directly for a human relaxin gene using an homologous porcine relaxin cDNA probe. We report here the successful identification of a genomic clone from which the structure of the entire coding region of a human preprorelaxin gene has been determined. Synthesis of biologically active relaxin has shown that the novel gene structure described herein codes for an authentic human relaxin. We believe this is the first successful synthesis of a biologically active hormone whose structure was predicted solely from the structure of a genomic clone.     

Correlation between acidic phospholipids and serotonin and between lysolecithin and dopamine in ganglia of the marine mussel,Mytilus edulis

Summary These studies have demonstrated a positive correlation between the acidic phospholipids and the serotonin content and between the lysolecithin and the dopamine content in the cerebral, pedal and visceral ganglia ofMytilus edulis. These relationships were further supported by experiments utilizing 6-hydroxydopamine and 5,6-dihydroxytryptamine.This study was partially supported by USPHS grant NS 10845 to Dr E. Aiello of Fordham University.Presently at Medgar Evers College of C.U.N.Y., Brooklyn, N.Y. 11225.     

Brain concentrations of LSD-25 (delysid) after intracerebral or intravenous administration in conscious animals

Zusammenfassung Die Radioaktivität in Gehirn, Leber und Dünndarm der Maus nach intravenöser und nach intrazerebraler Injektion von¹⁴C-Lysergsäure-diäthylamid (Delysid) wurde bestimmt. Es ergibt sich, dass die radioaktive Substanz nach intrazerebraler Injektion mindestens ebenso schnell in der Leber erscheint und durch die Galle in den Dünndarm ausgeschieden wird, als das bei intravenöser Anwendung der Fall ist. Da nach intravenöser Injektion des markierten Delysids nur eine minimale Aktivität im Gehirn erreicht wird, kann geschlossen werden, dass die Blut-Liquor-Schranke wohl den Übertritt des Delysides vom Blut ins Gehirn weitgehend hemmt, aber den Austritt der Verbindung aus dem Gehirn nicht behindert.Die schnelle Ausscheidung von¹⁴C-markiertem Delysid aus dem Gehirn nach intraventrikulärer Injektion wurde in Versuchen an der Katze bestätigt.     

Type II supernovae as a significant source of interstellar dust

Large amounts of dust (>10(8)M(o)) have recently been discovered in high-redshift quasars and galaxies corresponding to a time when the Universe was less than one-tenth of its present age. The stellar winds produced by stars in the late stages of their evolution (on the asymptotic giant branch of the Hertzsprung-Russell diagram) are thought to be the main source of dust in galaxies, but they cannot produce that dust on a short enough timescale (&<1 Gyr) to explain the results in the high-redshift galaxies. Supernova explosions of massive stars (type II) are also a potential source, with models predicting 0.2-4M(o) of dust. As massive stars evolve rapidly, on timescales of a few Myr, these supernovae could be responsible for the high-redshift dust. Observations of supernova remnants in the Milky Way, however, have hitherto revealed only 10(-7)-10(-3)M(o) each, which is insufficient to explain the high-redshift data. Here we report the detection of approximately 2-4M(o) of cold dust in the youngest known Galactic supernova remnant, Cassiopeia A. This observation implies that supernovae are at least as important as stellar winds in producing dust in our Galaxy and would have been the dominant source of dust at high redshifts.     

Veränderungen der elektrischen Hirntätigkeit bei Katzen nach Röntgentotalbestrahlung

Summary In cats with chronically implanted electrodes, hippocampus and amygdala consistently showed spike discharges immediately after relatively low doses of total body x-irradiation (400 r) and reticular arousal thresholds were transitorily decreased. Thalamic recruiting thresholds increased later, while hippocampal seizure thresholds remained practically unaltered. Experiments with lower doses are in progress.

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This article is based on work performed under Contract No. AT-(04-1)-GEN-12 between the Atomic Energy Commission and the University of California at Los Angeles.