c-Myc regulates mammalian body size by controlling cell number but not cell size.

Overexpression of the proto-oncogene c-myc has been implicated in the genesis of diverse human tumours. c-Myc seems to regulate diverse biological processes, but its role in tumorigenesis and normal physiology remains enigmatic. Here we report the generation of an allelic series of mice in which c-myc expression is incrementally reduced to zero. Fibroblasts from these mice show reduced proliferation and after complete loss of c-Myc function they exit the cell cycle. We show that Myc activity is not needed for cellular growth but does determine the percentage of activated T cells that re-enter the cell cycle. In vivo, reduction of c-Myc levels results in reduced body mass owing to multiorgan hypoplasia, in contrast to Drosophila c-myc mutants, which are smaller as a result of hypotrophy. We find that c-myc substitutes for c-myc in fibroblasts, indicating they have similar biological activities. This suggests there may be fundamental differences in the mechanisms by which mammals and insects control body size. We propose that in mammals c-Myc controls the decision to divide or not to divide and thereby functions as a crucial mediator of signals that determine organ and body size.     

MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.     

Strain-induced metal-insulator phase coexistence in perovskite manganites

The coexistence of distinct metallic and insulating electronic phases within the same sample of a perovskite manganite, such as La(1-x-y)Pr(y)Ca(x)MnO3, presents researchers with a tool for tuning the electronic properties in materials. In particular, colossal magnetoresistance in these materials--the dramatic reduction of resistivity in a magnetic field--is closely related to the observed texture owing to nanometre- and micrometre-scale inhomogeneities. Despite accumulated data from various high-resolution probes, a theoretical understanding for the existence of such inhomogeneities has been lacking. Mechanisms invoked so far, usually based on electronic mechanisms and chemical disorder, have been inadequate to describe the multiscale, multiphase coexistence within a unified picture. Moreover, lattice distortions and long-range strains are known to be important in the manganites. Here we show that the texturing can be due to the intrinsic complexity of a system with strong coupling between the electronic and elastic degrees of freedom. This leads to local energetically favourable configurations and provides a natural mechanism for the self-organized inhomogeneities over both nanometre and micrometre scales. The framework provides a physical understanding of various experimental results and a basis for engineering nanoscale patterns of metallic and insulating phases.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.     

Occurrence, distribution and nature of neuropeptide Y in the rat pancreas

Significant quantities of a newly discovered peptide, neuropeptide Y, were found in the rat pancreas, where they were localized to nerves in the exocrine parenchyma and around arterial and ductal structures. Although unaffected by surgical parasympathectomy, the periarterial and periductal nerves were abolished by chemical sympathectomy, suggesting that NPY is partially costored with sympathetic transmitters in nerve fibers.     

A cellular oncogene (c-Ki-ras) is amplified, overexpressed, and located within karyotypic abnormalities in mouse adrenocortical tumour cells

The cellular oncogene c-Ki-ras is amplified 30- to 60-fold in cells of the mouse adrenocortical tumour Y1. The amplified oncogene is located in double minute chromosomes and in a homogeneously staining chromosomal region, common karyotypical anomalies of tumour cells. The amounts of c-Ki-ras specific mRNA and of the protein (p21) encoded by the amplified gene are correspondingly elevated. Amplification and enhanced expression of cellular oncogenes may contribute to the genesis and/or maintenance of at least some naturally occurring tumours.     

The regulatory peptide system of the large bowel in equine grass sickness

Summary In recent years, distinct changes in regulatory peptides have been found in a number of gastrointestinal diseases. Grass sickness is a fatal disease of horses for which the etiology has yet to be fully ascertained. In this study, the peptide-containing nerves and ganglionic and mucosal endocrine cells of the ileum, colon and rectum were investigated in horses with sub-acute or chronic grass sickness and compared with normal controls using immunocytochemistry, at both the light and electron microscopical levels, and radioimmunoassay. A substantial loss of both peptide-containing cells and nerves was found in all of the sick horses, particularly in the ileum. Electron microscopy revealed marked degeneration of nerves in the gut wall. fibers containing granules immunostained for substance P or VIP, using the immunogold staining technique, underwent extensive degranulation in grass sickness, with the formation of multiple vacuoles.Radioimmunoassay of peptide content also showed that the most drastic changes occurred in the ileum. For example, VIP content was significantly reduced from 109±19.8 (mean±SEM) pmoles/g in controls to 6.8±1.4 pmoles/g in grass sickness (p<0.001) and substance P from 65.9±8.1 to 31.3±9.5 (p<0.02). These results may have applications in the diagnosis and treatment of grass sickness.The authors gratefully acknowledge the financial support of the Wellcome Trust and the Grass Sickness Fund.     

Hydrated silicate minerals on Mars observed by the Mars Reconnaissance Orbiter CRISM instrument

Phyllosilicates, a class of hydrous mineral first definitively identified on Mars by the OMEGA (Observatoire pour la Mineralogie, L'Eau, les Glaces et l'Activitié) instrument, preserve a record of the interaction of water with rocks on Mars. Global mapping showed that phyllosilicates are widespread but are apparently restricted to ancient terrains and a relatively narrow range of mineralogy (Fe/Mg and Al smectite clays). This was interpreted to indicate that phyllosilicate formation occurred during the Noachian (the earliest geological era of Mars), and that the conditions necessary for phyllosilicate formation (moderate to high pH and high water activity) were specific to surface environments during the earliest era of Mars's history. Here we report results from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) of phyllosilicate-rich regions. We expand the diversity of phyllosilicate mineralogy with the identification of kaolinite, chlorite and illite or muscovite, and a new class of hydrated silicate (hydrated silica). We observe diverse Fe/Mg-OH phyllosilicates and find that smectites such as nontronite and saponite are the most common, but chlorites are also present in some locations. Stratigraphic relationships in the Nili Fossae region show olivine-rich materials overlying phyllosilicate-bearing units, indicating the cessation of aqueous alteration before emplacement of the olivine-bearing unit. Hundreds of detections of Fe/Mg phyllosilicate in rims, ejecta and central peaks of craters in the southern highland Noachian cratered terrain indicate excavation of altered crust from depth. We also find phyllosilicate in sedimentary deposits clearly laid by water. These results point to a rich diversity of Noachian environments conducive to habitability.