Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In this study, we analyzed tissue factor (TF) expression in four different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that two of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Importantly, only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF antibody. Of the two TF-positive lines only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly,<5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor bearing and control mice in an inferior vena cava stenosis model. Our studies suggest that in a xenograft mouse model tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.

The enhancement of radiodamage to DNA labelled with halonucleobases is attributed to the reactive radical produced from a halonucleobase by the attachment of an electron. We examined at the B3LYP/6-31++G** level electron capture by four brominated nucleobases (BrNBs): 8-bromo-9-methyladenine, 8-bromo-9-methylguanine, 5-bromo-1-methylcytosine and 5-bromo-1-methyluracil followed by the release of the bromide anion and a nucleobase radical. We demonstrate that neutral BrNBs in both, gas and aqueous phases, are better electron acceptors than unsubstituted NBs and that resulting anion radicals, BrNBs•-, can easily transform into product complex of bromide anion and the nucleobase radical ([Br-•••NB•]). The overall thermodynamic stimulus for the process starting with the neutral BrNB and ending with the isolated bromide anion and the NB• radical is similar in case of all four BrNBs studied, which suggests their comparable radiosensitizing capabilities.

The yield of charged particles associated with high-p_{t} trigger particles (8<p_{t}<15  GeV/c) is measured with the ALICE detector in Pb-Pb collisions at sqrt[s_{NN}]=2.76  TeV relative to proton-proton collisions at the same energy. The conditional per-trigger yields are extracted from the narrow jetlike correlation peaks in azimuthal dihadron correlations. In the 5% most central collisions, we observe that the yield of associated charged particles with transverse momenta p_{t}>3  GeV/c on the away side drops to about 60% of that observed in pp collisions, while on the near side a moderate enhancement of 20%-30% is found.

The ALICE Collaboration has studied J/ψ production in pp collisions at sqrt[s]=7  TeV at the LHC through its muon pair decay. The polar and azimuthal angle distributions of the decay muons were measured, and results on the J/ψ polarization parameters λ_{θ} and λ_{ϕ} were obtained. The study was performed in the kinematic region 2.5<y<4, 2<p_{t}<8  GeV/c, in the helicity and Collins-Soper reference frames. In both frames, the polarization parameters are compatible with zero, within uncertainties.

Once regarded as cellular 'debris' extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers.

A new series of low-melting quaternary ammonium salts based on a glycolated cobalt bis(dicarbollide) anion structure have been synthesized and characterized, and their spectroscopic and physicochemical properties have been studied. The lowest melting point was obtained for 1-butyl-3-methylimidazolium (∼50 °C) followed by 1-butyl-1-methylpiperidinium (∼80 °C), 1-butyl-1-methylpyrrolidinium (∼95 °C), and 1-butyl-4-methylpyridinium salts (∼115 °C). The salts were thermally stable up to 180 °C [decomposition of an oligo(ethylene glycol) chain] and contained variable amounts of water. The flexible oligo(ethylene glycol) chains contributed to the waxy state of salts. The solubility of the salts was determined for 76 solvents that are commonly used in organic chemistry. Generally, the solubility increased with the dipole moment and relative polarity of the solvent. Salts exhibited good solubility in ketones and esters; moderate solubility was observed in alcohols, aromates, and chlorinated solvents, and poor solubility was obtained in ethers. The salts were practically insoluble in higher hydrocarbons and water. Salts are dissolved in the form of ion pairs or separated ions, depending on the nature of the solvent.

Patients with end stage renal diseases (ESRD) are generally tested for donor chimerism after kidney transplantation for tolerance mechanism purposes. But, to our knowledge, no data are available on natural and/or iatrogenic microchimerism (Mc), deriving from pregnancy and/or blood transfusion, acquired prior to transplantation. In this context, we tested the prevalence of male Mc using a real time PCR assay for DYS14, a Y-chromosome specific sequence, in peripheral blood mononuclear cells (PBMC) from 55 women with ESRD, prior to their first kidney transplantation, and compared them with results from 82 healthy women. Male Mc was also quantified in 5 native kidney biopsies obtained two to four years prior to blood testing and in PBMC from 8 women collected after female kidney transplantation, several years after the initial blood testing. Women with ESRD showed statistically higher frequencies (62%) and quantities (98 genome equivalent cells per million of host cells, gEq/M) of male Mc in their PBMC than healthy women (16% and 0.3 gEq/M, p<0.00001 and p = 0.0005 respectively). Male Mc was increased in women with ESRD whether they had or not a history of male pregnancy and/or of blood transfusion. Three out of five renal biopsies obtained a few years prior to the blood test also contained Mc, but no correlation could be established between earlier Mc in a kidney and later presence in PBMC. Finally, several years after female kidney transplantation, male Mc was totally cleared from PBMC in all women tested but one. This intriguing and striking initial result of natural and iatrogenic male Mc persistence in peripheral blood from women with ESRD raises several hypotheses for the possible role of these cells in renal diseases. Further studies are needed to elucidate mechanisms of recruitment and persistence of Mc in women with ESRD.

We measured the low energy electron stimulated desorption (ESD) of anions from thin films of native (TXT) and bromine monosubstituted (TBrXT) oligonucleotide trimers deposited on a gold surface (T = thymidine, X = T, deoxycytidine (C), deoxyadenosine (A) or deoxyguanosine (G), Br = bromine). The desorption of H(-), CH(3)(-)∕NH(-), O(-)∕NH(2)(-), OH(-), CN(-), and Br(-) was induced by 0 to 20 eV electrons. Dissociative electron attachment, below 12 eV, and dipolar dissociation, above 12 eV, are responsible for the formation of these anions. The comparison of the results obtained for the native and brominated trimers suggests that the main pathways of TBrXT degradation correspond to the release of the hydride and bromide anions. Significantly, the presence of bromine in oligonucleotide trimers blocks the electron-induced degradation of nuclobases as evidenced by a dramatic decrease in CN(-) desorption. An increase in the yields of OH(-) is also observed. The debromination yield of particular oligonucleotides diminishes in the following order: BrdU > BrdA > BrdG > BrdC. Based on these results, 5-bromo-2(')-deoxyuridine appears to be the best radiosensitizer among the studied bromonucleosides.

Tumour progression is continuously driven by a sequence of genetic events. The presence of mutant or activated Ras proteins represents an interesting paradigm for the investigation of oncogene-dependent induction of tumour angiogenesis. These genes are widely distributed in human cancers. Previously we have shown that cells harbouring mutant H-Ras release soluble unidentified factor(s) associated with lowered expression of an angiogenesis inhibitor - Thrombospondin-1 -(TSP-1) in adjacent normal tissue. In this study, we have addressed the question as to whether or not introduction of the H-ras oncogene leads to increased production of sphingosine. To assess the amount of sphingosine in conditioned media, we developed a technique based on sphingolipid isolation and GC-MSMS detection of specific silylated sphingosine derivatives. Cells harbouring mutant H-Ras, release significant amounts of sphingosine in contrast to normal isogenic cells or premalignant cells. Increased concentration of sphingosine in conditioned media was correlated with their ability to down-regulate the expression of TSP-1. Moreover, medium collected in the presence of U0126, an inhibitor of MAPK kinase (MEK), contained undetectable amounts of sphingosine and had no ability to down-regulate TSP-1 expression. Overall, our studies suggest a H-Ras-dependent mechanism of changing the equilibrium of angiogenic factors in favour of induction of angiogenesis, where a central role is played by sphingosine, a low molecular entity. This represents an example of how a mechanism of translating genetic changes within transformed cells could be amplified into a much larger effect involving the tumour parenchyma and stroma, and this could greatly in turn accelerate local tumour growth and metastasis.

VEGF-C and VEGF-D have been implicated in lymphatic metastasis, mainly as inducers of new intra/peritumoral capillary lymphatics. In this issue of Cancer Cell, Karnezis and colleagues challenge this notion and demonstrate that tumor-derived VEGF-D promotes metastasis by causing prostaglandin-dependent dilation of collecting lymphatics outside of the tumor mass.