Oncogenic pathway signatures in human cancers as a guide to targeted therapies

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.     

Noise induced convulsions in mice

Zusammenfassung Es wird die Anzahl der Krampfanfälle bestimmt, die durch intensiven niederfrequenten (135 db, 300–4800 Hz) und hochfrequenten (132 db, 2–40 kHz) Schall bei Mäusen ausgelöst werden. Die Krampfschwelle ist bei hohen Frequenzen wesentlich geringer als bei niedrigen. Dieses Ergebnis stimmt mit Berichten, dass die optimale Sensitivität von Nagetieren bei 12–25 kHz liegt, überein.     

GTPase activity of dynamin and resulting conformation change are essential for endocytosis

Dynamin is a large GTPase with a relative molecular mass of 96,000 (Mr 96K) that is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Although its function is apparently essential for scission of newly formed vesicles from the plasma membrane, the nature of dynamin's role in the scission process is still unclear. It has been proposed that dynamin is a regulator (similar to classical G proteins) of downstream effectors. Here we report the analysis of several point mutants of dynamin's GTPase effector (GED) and GTPase domains. We show that oligomerization and GTP binding alone, by dynamin, are not sufficient for endocytosis in vivo. Rather, efficient GTP hydrolysis and an associated conformational change are also required. These data argue that dynamin has a mechanochemical function in vesicle scission.     

Possible relationship between packed sperm volume and egg mass in domestic fowl

Summary Packed sperm volume (PSV) values of male chickens have been observed to parallel the daily egg mass values of laying hens. Selection progress was greater when selection was for PSV and egg mass than for egg mass alone.     

Summer habitat use by Columbian Sharp-tailed Grouse in western Idaho

We studied summer habitat use by Columbian Sharp-tailed Grouse ( Tympanuchus phasianellus columbianus ) in western Idaho during 1983-85. Vegetative and topographic measurements were recorded at 716 locations of 15 radio-tagged grouse and at 180 random sites within the major vegetation/cover types in the study area. The mean size of summer home ranges was 1.87 ± 1.14 km 2 . Of eight cover types identified in the study area, individual grouse used the big sagebrush Artemisia tridentata ) cover type more than or in proportion to availability, the low sagebrush ( A. arbuscula ) in proportion to availability, and avoided the shrubby eriogonum ( Eriogonum spp.) type. Characteristics of the big sagebrush cover type that Sharp-tailed Grouse preferred include moderate vegetative cover, high plant species diversity, and high structural diversity. Grouse used areas of dense cover (i.e., mountain shrub and riparian cover types) primarily for escape cover. Compared with random sites, grouse selected areas with (1) greater horizontal and vertical cover, (2) greater canopy coverage of forbs typically decreased by livestock grazing, (3) greater density and canopy coverage of arrowleaf balsamroot ( Balsamorhiza sagittata ), and (4) greater canopy coverage of bluebunch wheatgrass ( Agropyron spicatum ) in the big sagebrush cover type in 1984 and the low sagebrush cover type in 1985. The importance of the native perennials arrowleaf balsamroot and bluebunch wheatgrass became apparent during a drought year when many exotic annuals dried up and provided no cover. Overall, grouse selected vegetative communities that were least modified by livestock grazing.     

Clostridial neurotoxins: structure-function led design of new therapeutics

The neurotoxins produced by various species of Clostridia are the causative agents of botulism and tetanus. The ability of the toxins, specifically those of the botulinum neurotoxin family, to disrupt neurotransmission has been exploited for use in several medical indications and now represents the therapeutic option of choice in a number of cases. Clostridial neurotoxins have been discovered to have a multi-domain structure that is shared between the various proteins of the family, and it has also been determined that each domain contributes a specific role to the holotoxin. The extensive use of recombinant expression approaches, along with solution of multiple crystallographic structures of individual domains, has enabled researchers to explore structurefunction relationships of the toxin domains more closely. These advances have facilitated a greater understanding of the potential use of individual domains for a wide variety of purposes, including the development of new therapeutics. Received 21 October 2005; received after revision 10 November 2005; accepted 16 November 2005