Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis

Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2$\alpha$ in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.Research was supported through a Wellcome Trust Principal Research Fellowship to R.S.J. (RG59596). C.B. is supported through a Scientific Fellowship from Breast Cancer Now (2014MaySF275). C.E.E. received a Pump-Priming Grant from the University of Cambridge British Heart Foundation Centre of Research Excellence (RG68639)

Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B

Background: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. Results: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. Conclusions: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease

Resolved Photon Processes

We review the present level of knowledge of the hadronic structure of the photon, as revealed in interactions involving quarks and gluons ``in" the photon. The concept of photon structure functions is introduced in the description of deep--inelastic $e \gamma$ scattering, and existing parametrizations of the parton densities in the photon are reviewed. We then turn to hard \gamp\ and \gaga\ collisions, where we treat the production of jets, heavy quarks, hard (direct) photons, \jpsi\ mesons, and lepton pairs. We also comment on issues that go beyond perturbation theory, including recent attempts at a comprehensive description of both hard and soft \gamp\ and \gaga\ interactions. We conclude with a list of open problems.Comment: LaTeX with equation.sty, 85 pages, 29 figures (not included). A complete PS file of the paper, including figures, can be obtained via anonymous ftp from ftp://phenom.physics.wisc.edu/pub/preprints/1995/madph-95-898.ps.

Phylogenetic representativeness: a new method for evaluating taxon sampling in evolutionary studies

<p>Abstract</p> <p>Background</p> <p>Taxon sampling is a major concern in phylogenetic studies. Incomplete, biased, or improper taxon sampling can lead to misleading results in reconstructing evolutionary relationships. Several theoretical methods are available to optimize taxon choice in phylogenetic analyses. However, most involve some knowledge about the genetic relationships of the group of interest (i.e., the ingroup), or even a well-established phylogeny itself; these data are not always available in general phylogenetic applications.</p> <p>Results</p> <p>We propose a new method to assess taxon sampling developing Clarke and Warwick statistics. This method aims to measure the "phylogenetic representativeness" of a given sample or set of samples and it is based entirely on the pre-existing available taxonomy of the ingroup, which is commonly known to investigators. Moreover, our method also accounts for instability and discordance in taxonomies. A Python-based script suite, called PhyRe, has been developed to implement all analyses we describe in this paper.</p> <p>Conclusions</p> <p>We show that this method is sensitive and allows direct discrimination between representative and unrepresentative samples. It is also informative about the addition of taxa to improve taxonomic coverage of the ingroup. Provided that the investigators' expertise is mandatory in this field, phylogenetic representativeness makes up an objective touchstone in planning phylogenetic studies.</p