Applying unmixing to gene expression data for tumor phylogeny inference

<p>Abstract</p> <p>Background</p> <p>While in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity.</p> <p>Results</p> <p>The present work applies "unmixing" methods, which separate complex data sets into combinations of simpler components, to attempt to gain advantages of both tissue-wide and single-cell approaches to cancer phylogenetics. We develop an unmixing method to infer recurring cell states from microarray measurements of tumor populations and use the inferred mixtures of states in individual tumors to identify possible evolutionary relationships among tumor cells. Validation on simulated data shows the method can accurately separate small numbers of cell states and infer phylogenetic relationships among them. Application to a lung cancer dataset shows that the method can identify cell states corresponding to common lung tumor types and suggest possible evolutionary relationships among them that show good correspondence with our current understanding of lung tumor development.</p> <p>Conclusions</p> <p>Unmixing methods provide a way to make use of both intra-tumor heterogeneity and large probe sets for tumor phylogeny inference, establishing a new avenue towards the construction of detailed, accurate portraits of common tumor sub-types and the mechanisms by which they develop. These reconstructions are likely to have future value in discovering and diagnosing novel cancer sub-types and in identifying targets for therapeutic development.</p

C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma

Members of the Fos protein family dimerise with Jun proteins to form the AP-1 transcription factor complex. They have a central function in proliferation and differentiation of normal tissue as well as in oncogenic transformation and tumour progression. We analysed the expression of c-Fos, FosB, Fra-1 and Fra-2 to investigate the function of Fos transcription factors in ovarian cancer. A total of 101 patients were included in the study. Expression of Fos proteins was determined by western blot analysis, quantified by densitometry and verified by immunohistochemistry. Reduced c-Fos expression was independently associated with unfavourable progression-free survival (20.6, 31.6 and 51.2 months for patients with low, moderate and high c-Fos expression; P=0.003) as well as overall survival (23.8, 46.0 and 55.5 months for low, moderate and high c-Fos levels; P=0.003). No correlations were observed for FosB, Fra-1 and Fra-2. We conclude that loss of c-Fos expression is associated with tumour progression in ovarian carcinoma and that c-Fos may be a prognostic factor. These results are in contrast to the classic concept of c-Fos as an oncogene, but are supported by the recently discovered tumour-suppressing and proapoptotic function of c-Fos in various cancer types

Uptake of catamphiphilic drugs into erythrocytes and muscular tissue correlates to membrane enrichment and to ca-45 displacement from phosphatidylserine monolayers

The uptake of the catamphiphilic drugs flunarizine, R 56865 [N-1-4-(4-fluorophenoxy)butyl-4-piperidinyl-N-methyl-2-benzothia- zolamine], verapamil, diltiazem, lidocaine and the noncatamphiphilic drug nitrendipine into erythrocytes and erythrocyte membranes was measured at pH 7.2 in a Ringer's solution at 22°C. The uptake was concentration proportional between 10-8and 10-6mol/l for all drugs investigated; the erythrocyte/medium ratio (E/M) was constant after 20 min in all experiments. In rat aortas and left atria drug uptake was measured in a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffered medium (pH 7.2, 32°C). Equilibrium was reached after 360 min and the tissue/medium ratio (T/M) was concentration proportional between 10-8and 10-6mol/l for all drugs. E/M or T/M ratios, respectively, increased in the order: erythrocytes <aortas <left atria. However, the particular drug/phospholipid ratios were relatively constant for the drugs investigated, indicating that the membranes were a major distribution phase for these drugs. For the catamphiphilic drugs, the E/M or T/M ratios correlated linearly with the EC50for45Ca displacement from phosphatidylserine monolayers, but were poorly correlated with the octanol-water coefficient of the uncharged molecules. The EC50for45Ca displacement from phosphatidylserine monolayers is a measure for the uptake of the protonated species of catamphiphilic drugs into erythrocytes or tissue and may be a good estimate of tissue uptake of these drugs in general

Cowdriosis/Heartwater

Heartwater (or cowdriosis) is a tick-borne disease caused by Ehrlichia ruminantium, an obligatory intracellular bacterium of the order Rickettsiales, transmitted by several ticks of the genus Amblyomma. The organism is genetically highly variable which prevented until now the development of efficient vaccines. The disease is enzootic in sub-Sahelian Africa and in some Caribbean islands. It affects domestic and wild ruminants, the susceptibility to cowdriosis varying greatly between breeds and species: African wildlife shows mainly asymptomatic infections; local cattle breeds are generally protected due to enzootic stability; and introduced cattle breeds and small ruminants, even in enzootic regions, are usually susceptible to heartwater and can suffer high mortality rates. Cowdriosis is characterized by a sudden and acute fever followed by nervous, respiratory, and gastrointestinal symptoms and by hydrothorax and hydropericardium during postmortem examination. In West Africa, the only vector is Amblyomma variegatum, present in areas where pluviometry is higher than 500 mm. Therefore, animals of a high proportion of the Sahelian region are usually not infested by the tick and not infected by the bacterium. They are thus susceptible when introduced in southern parts of the Sahel or in the subhumid neighboring areas of the West African countries, for example during transhumance. Tetracyclines are effective drugs to treat heartwater when administered before occurrence of the nervous symptoms. Various vaccines have been tested, and are still developed, but, up to now, none of them showed enough effectiveness against all the field strains of E. ruminantium to allow its marketing. Prevention is therefore mainly achieved by drastic vector control or, on the contrary, acquisition of enzootic stability following tick infestation combined with tetracycline treatment as soon as hyperthermia occurs