Gene expression profiling predicts clinical outcome of breast cancer

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.     

Philosophy and history of science: Beyond the Kuhnian paradigm

At issue in this paper is the question of the appropriate relationship between the philosophy and history of science. The discussion starts with a brief sketch of Kuhn's approach, followed by an analysis of the so-called ‘testing-theories-of-scientific-change programme’. This programme is an attempt at a more rigorous approach to the historical philosophy of science. Since my conclusion is that, by and large, this attempt has failed, I proceed to examine some more promising approaches. First, I deal with Hacking's recent views on the issues in question, particularly his notion of a ‘style of reasoning’. Next, Nickles's reconstructionist interpretation of the development of science and his views on Whig history are addressed. Finally, I propose an account of philosophy as a theoretical, an interpretative and explanatory, enterprise. Thus, three alternatives to the Kuhnian paradigm are discussed, alternatives that share a recognition of the relative autonomy of philosophy from history. Hence, they assume a less tight relationship between philosophy and history of science than is the case within the Kuhnian paradigm.     

Raf-1 activates MAP kinase-kinase.

The normal cellular homologue of the acutely transforming oncogene v-raf is c-raf-1, which encodes a serine/threonine protein kinase that is activated by many extracellular stimuli. The physiological substrates of the protein c-Raf-1 are unknown. The mitogen-activated protein (MAP) kinases Erk1 and 2 are also activated by mitogens through phosphorylation of Erk tyrosine and threonine residues catalysed by a protein kinase of relative molecular mass 50,000, MAP kinase-kinase (MAPK-K). Here we report that MAPK-K as well as Erk1 and 2 are constitutively active in v-raf-transformed cells. MAPK-K partially purified from v-raf-transformed cells or from mitogen-treated cells can be deactivated by phosphatase 2A. c-Raf-1 purified after mitogen stimulation can reactivate the phosphatase 2A-inactivated MAPK-K over 30-fold in vitro. c-Raf-1 reactivation of MAPK-K coincides with the selective phosphorylation at serine/threonine residues of a polypeptide with M(r) 50,000 which coelutes precisely on cation-exchange chromatography with the MAPK-K activatable by c-Raf-1. These results indicate that c-Raf-1 is an immediate upstream activator of MAPK-K in vivo. To our knowledge, MAPK-K is the first physiological substrate of the c-raf-1 protooncogene product to be identified.     

Mutation und Phänokopie bei Säugetier und Mensch

Summary The concept of phenocopy established byGoldschmidt in 1935 is critically studied and special emphasis is placed upon the problem of how to distinguish true and false phenocopies. A comparison is made with true and false genocopies, that means mimic mutations. Regarding a given character it is often hard to distinguish as far as man and mammals are concerned, whether it is caused by mutation or phenocopy. Although most of the abnormalities occur as hereditary as well as non-hereditary types, there are, however, hereditary defects that occur seldom and others that occur frequently as phenocopies; still other abnormalities are known as yet only as non-hereditary modifications. It is still impossible to give exact figures for the numerical relationship of single hereditary and non-hereditary abnormalities in man.In certain cases in man and animals there may be also an interaction of the gene and the phenocopying agent, the latter replacing the missing second allele of the gene in question in a heterozygotic individual. The question has to be examined whether in the case of horizontal inheritance, that means occurrence of the same character only in one sibship, a hereditary effect is only simulated with the same phenocopying factor continually in effect. Finally a method is given to determine the relationship of mutations and phenocopies of the retinoblastoma, a hereditary or exogenous caused highly malignant ocular neoplasm in man, a question very important to eugenics.

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Dem PathologenRobert Rössle* zum 80. Geburtstag am 19. August 1956 gewidmet

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Redaktionelle Anmerkung. Am 21. November 1956 ist Herr Prof.Rössle in Berlin verstorben. Die Experientia-Leser erinnern sich dankbar an seinen Aufsatz: «Warum sterben so wenig Menschen eines natürlichen Todes?» Exper.4, 295 (1948).

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Nach einem Vortrag an der Universität Nagoya (Japan) am 17. September 1956.     

Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA

Repair of DNA damage is essential for maintaining genome integrity, and repair deficiencies in mammals are associated with cancer, neurological disease and developmental defects. Alkylation damage in DNA is repaired by at least three different mechanisms, including damage reversal by oxidative demethylation of 1-methyladenine and 3-methylcytosine by Escherichia coli AlkB. By contrast, little is known about consequences and cellular handling of alkylation damage to RNA. Here we show that two human AlkB homologues, hABH2 and hABH3, also are oxidative DNA demethylases and that AlkB and hABH3, but not hABH2, also repair RNA. Whereas AlkB and hABH3 prefer single-stranded nucleic acids, hABH2 acts more efficiently on double-stranded DNA. In addition, AlkB and hABH3 expressed in E. coli reactivate methylated RNA bacteriophage MS2 in vivo, illustrating the biological relevance of this repair activity and establishing RNA repair as a potentially important defence mechanism in living cells. The different catalytic properties and the different subnuclear localization patterns shown by the human homologues indicate that hABH2 and hABH3 have distinct roles in the cellular response to alkylation damage.     

An ultraslow-spreading class of ocean ridge

New investigations of the Southwest Indian and Arctic ridges reveal an ultraslow-spreading class of ocean ridge that is characterized by intermittent volcanism and a lack of transform faults. We find that the mantle beneath such ridges is emplaced continuously to the seafloor over large regions. The differences between ultraslow- and slow-spreading ridges are as great as those between slow- and fast-spreading ridges. The ultraslow-spreading ridges usually form at full spreading rates less than about 12 mm yr(-1), though their characteristics are commonly found at rates up to approximately 20 mm yr(-1). The ultraslow-spreading ridges consist of linked magmatic and amagmatic accretionary ridge segments. The amagmatic segments are a previously unrecognized class of accretionary plate boundary structure and can assume any orientation, with angles relative to the spreading direction ranging from orthogonal to acute. These amagmatic segments sometimes coexist with magmatic ridge segments for millions of years to form stable plate boundaries, or may displace or be displaced by transforms and magmatic ridge segments as spreading rate, mantle thermal structure and ridge geometry change.     

SNARE-protein-mediated disease resistance at the plant cell wall

Failure of pathogenic fungi to breach the plant cell wall constitutes a major component of immunity of non-host plant species--species outside the pathogen host range--and accounts for a proportion of aborted infection attempts on 'susceptible' host plants (basal resistance). Neither form of penetration resistance is understood at the molecular level. We developed a screen for penetration (pen) mutants of Arabidopsis, which are disabled in non-host penetration resistance against barley powdery mildew, Blumeria graminis f. sp. hordei, and we isolated the PEN1 gene. We also isolated barley ROR2 (ref. 2), which is required for basal penetration resistance against B. g. hordei. The genes encode functionally homologous syntaxins, demonstrating a mechanistic link between non-host resistance and basal penetration resistance in monocotyledons and dicotyledons. We show that resistance in barley requires a SNAP-25 (synaptosome-associated protein, molecular mass 25 kDa) homologue capable of forming a binary SNAP receptor (SNARE) complex with ROR2. Genetic control of vesicle behaviour at penetration sites, and plasma membrane location of PEN1/ROR2, is consistent with a proposed involvement of SNARE-complex-mediated exocytosis and/or homotypic vesicle fusion events in resistance. Functions associated with SNARE-dependent penetration resistance are dispensable for immunity mediated by race-specific resistance (R) genes, highlighting fundamental differences between these two resistance forms.     

Experimental evidence for sub-3-fs charge transfer from an aromatic adsorbate to a semiconductor

The ultrafast timescale of electron transfer processes is crucial to their role in many biological systems and technological devices. In dye-sensitized solar cells, the electron transfer from photo-excited dye molecules to nanostructured semiconductor substrates needs to be sufficiently fast to compete effectively against loss processes and thus achieve high solar energy conversion efficiencies. Time-resolved laser techniques indicate an upper limit of 20 to 100 femtoseconds for the time needed to inject an electron from a dye into a semiconductor, which corresponds to the timescale on which competing processes such as charge redistribution and intramolecular thermalization of excited states occur. Here we use resonant photoemission spectroscopy, which has previously been used to monitor electron transfer in simple systems with an order-of-magnitude improvement in time resolution, to show that electron transfer from an aromatic adsorbate to a TiO(2) semiconductor surface can occur in less than 3 fs. These results directly confirm that electronic coupling of the aromatic molecule to its substrate is sufficiently strong to suppress competing processes.     

Sperm from neonatal mammalian testes grafted in mice

Spermatogenesis is a productive and highly organized process that generates virtually unlimited numbers of sperm during adulthood. Continuous proliferation and differentiation of germ cells occur in a delicate balance with other testicular compartments, especially the supporting Sertoli cells. Many complex aspects of testis function in humans and large animals have remained elusive because of a lack of suitable in vitro or in vivo models. Germ cell transplantation has produced complete donor-derived spermatogenesis in rodents but not in other mammalian species. Production of sperm in grafted tissue from immature mammalian testes and across species has not yet been accomplished. Here we report the establishment of complete spermatogenesis by grafting testis tissue from newborn mice, pigs or goats into mouse hosts. This approach maintains structural integrity and provides the accessibility that is essential for studying and manipulating the function of testes and for preserving the male germ line. Our results indicate that this approach is applicable to diverse mammalian species.     

Copepod hatching success in marine ecosystems with high diatom concentrations

Diatoms dominate spring bloom phytoplankton assemblages in temperate waters and coastal upwelling regions of the global ocean. Copepods usually dominate the zooplankton in these regions and are the prey of many larval fish species. Recent laboratory studies suggest that diatoms may have a deleterious effect on the success of copepod egg hatching. These findings challenge the classical view of marine food-web energy flow from diatoms to fish by means of copepods. Egg mortality is an important factor in copepod population dynamics, thus, if diatoms have a deleterious in situ effect, paradoxically, high diatom abundance could limit secondary production. Therefore, the current understanding of energy transfer from primary production to fisheries in some of the most productive and economically important marine ecosystems may be seriously flawed. Here we present in situ estimates of copepod egg hatching success from twelve globally distributed areas, where diatoms dominate the phytoplankton assemblage. We did not observe a negative relationship between copepod egg hatching success and either diatom biomass or dominance in the microplankton in any of these regions. The classical model for diatom-dominated system remains valid.