Effects of puromycin on rat embryos in vitro

Somite-staged rat embryos were exposed to varying concentrations of puromycin for 48 h in vitro. Medium concentrations below 0.92 microM had no significant effects, while concentrations above 1.84 microM were lethal. Between these extremes, there were concentration dependent increases in the incidence of malformations in a close relationship to growth retardation.     

Inhibitory effects of nitrososarcosine on mouse liver mixed function oxidase activity

Zusammenfassung Nachweis, dass Nitrosarcosin im Gegensatz zu Dimethyl- und Dibutylnitrosamin die nichtfunktionelle Oxidase in der Mäuseleber hemmt.

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This work was supported by N.I.E.H.S. grant No. ES 00713.

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We are indebted to the technical help of Ms.Heather McClanahan.     

Monospecific antibody plaque formation by spleen cells from mice immunized with sheep and chicken erythrocytes

Zusammenfassung Milzzellenaufschwemmungen von Mäusen, die mit einem Gemisch von Schaf- und Hühnererythrocyten einmal injiziert wurden, verursachen lokalisierte, hämolytische Zonen (antibody plaques), die nicht aus den beiden Zelltypen, sondern entweder nur aus Schaf- oder nur aus Hühnerzellen bestehen. Lymphatische Zellen, die gleichzeitig zwei verschiedene Hämolysine abscheiden können, sind in Milzzellenaufschwemmungen von zweifach immunisierten Mäusen anscheinend abwesend oder nur in ganz geringer Anzahl vorhanden.

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The capable technical assistance of Mrs.Leony Mills during these studies is acknowledged. This investigation was supported in part by the U.S. National Science Foundation (Grant G-19581).     

Un développement nouveau de la lyophilisation: La cryodessiccation des systèmes non aqueux

Summary A new development is made to enlarge the field of lyophilization using non-aqueous media. Unstable compounds are preserved by freezing and drying their solutions in organic solvents. The same technique applied to chemicals dissolved in liquid ammonia enables the preparation of stable concentrated free radicals, due to the very low temperature of sublimation of frozen NH₃. Finally, experiments are made demonstrating the possibilities of high velocity, low temperature sublimation of solutions in solid CO₂ at normal atmospheric pressure.      

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.     

Differential Notch signalling distinguishes neural stem cells from intermediate progenitors

During brain development, neurons and glia are generated from a germinal zone containing both neural stem cells (NSCs) and more limited intermediate neural progenitors (INPs). The signalling events that distinguish between these two proliferative neural cell types remain poorly understood. The Notch signalling pathway is known to maintain NSC character and to inhibit neurogenesis, although little is known about the role of Notch signalling in INPs. Here we show that both NSCs and INPs respond to Notch receptor activation, but that NSCs signal through the canonical Notch effector C-promoter binding factor 1 (CBF1), whereas INPs have attenuated CBF1 signalling. Furthermore, whereas knockdown of CBF1 promotes the conversion of NSCs to INPs, activation of CBF1 is insufficient to convert INPs back to NSCs. Using both transgenic and transient in vivo reporter assays we show that NSCs and INPs coexist in the telencephalic ventricular zone and that they can be prospectively separated on the basis of CBF1 activity. Furthermore, using in vivo transplantation we show that whereas NSCs generate neurons, astrocytes and oligodendrocytes at similar frequencies, INPs are predominantly neurogenic. Together with previous work on haematopoietic stem cells, this study suggests that the use or blockade of the CBF1 cascade downstream of Notch is a general feature distinguishing stem cells from more limited progenitors in a variety of tissues.