Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Tritium breeding capability of water cooled ceramic breeder blanket with different container designs

Water cooled ceramic breeder (WCCB) blankets have been regarded as a primary concept in Japan. We in-vestigated the tritium breeding capability of a WCCB blanket with a cylindrical structure, an advantageous shapefor withstanding high coolant pressure, in this study. The breeding area in the blanket was modeled as ahomogeneous mixture or heterogeneous structures. Nuclear analyses with Monte Carlo method were conductedfor evaluating the tritium breeding ratio (TBR) of the blanket. The neutron balance of the blanket was analyzedto elucidate the mechanism related to the increase in TBR when an additional thin breeding layer (envelope) wasapplied to the blanket. The neutron multiplication in (n, 2n) reaction increased concomitantly with increase ofthe beryllium volume ratio. However, numerous neutrons were not used efficiently for tritium production, butwere captured by the container, which was made of the reduced activation ferritic martensitic steel, F82H.Capture by the container can be reduced by introducing an envelope. The effect of the envelope was considerablewhen modeling the internal structure such as U-shaped pipes in the breeding area. The envelope was also appliedto a blanket with different container designs. An increase in TBR was shown irrespective of blanket design. Theenvelope effect was remarkable when it was difficult to achieve the internal configuration, which was equivalentto the homogeneous mixture in the breeding are

Nuclear responses of WCCB TBM with different container designs

In test blanket module (TBM) program blanket major functions, which are tritium production, heat extraction for electric power production, and neutron shielding, will be demonstrated under fusion reactor environments in ITER. National Institutes for Quantum and Radiological Science and Technology (QST) has performed developments of water cooled ceramic breeder (WCCB) TBM as a primary concept in Japan. The container design of WCCB TBM was changed from the Box-shaped to a cylindrical structure to increase tritium breeding capability while maintaining pressure resistance under In-Box LOCA caused by water ingress into the container. The nuclear responses related to the blanket major functions would be changed with the container design change. The nuclear responses of WCCB TBM with the container design change were evaluated and the effects of the changed nuclear responses were described in this study. Tritium production rate increased by about 2 times with the container design changes. In contrast neutron shielding performance decreased due to the container design change. Degradation of neutron shielding in the cylindrical TBM led to an increase in nuclear heating of the TBM frame as well as an average of neuron flux behind TBM-set