On static spherically symmetric solutions of the vacuum Brans-Dicke theory

It is shown that among the four classes of the static spherically symmetric solution of the vacuum Brans-Dicke theory of gravity only two are really independent. Further by matching exterior and interior (due to physically reasonable spherically symmetric matter source) scalar fields it is found that only Brans class I solution with certain restriction on solution parameters may represent exterior metric for a nonsingular massive object. The physical viability of the black hole nature of the solution is investigated. It is concluded that no physical black hole solution different from the Schwarzschild black hole is available in the Brans-Dicke theory.Comment: 15 pages, To be published in Gen. Rel. and Grav, typos in references correcte

On Traversable Lorentzian Wormholes in the Vacuum Low Energy Effective String Theory in Einstein and Jordan Frames

Three new classes (II-IV) of solutions of the vacuum low energy effective string theory in four dimensions are derived. Wormhole solutions are investigated in those solutions including the class I case both in the Einstein and in the Jordan (string) frame. It turns out that, of the eight classes of solutions investigated (four in the Einstein frame and four in the corresponding string frame), massive Lorentzian traversable wormholes exist in five classes. Nontrivial massless limit exists only in class I Einstein frame solution while none at all exists in the string frame. An investigation of test scalar charge motion in the class I solution in the two frames is carried out by using the Plebanski-Sawicki theorem. A curious consequence is that the motion around the extremal zero (Keplerian) mass configuration leads, as a result of scalar-scalar interaction, to a new hypothetical "mass" that confines test scalar charges in bound orbits, but does not interact with neutral test particles.Comment: 18 page

Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Evading innate immunity in nonviral mRNA delivery : don't shoot the messenger

In de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications

Effect of acute kidney injury requiring extended dialysis on 28 day and 1 year survival of patients undergoing interventional lung assist membrane ventilator treatment

<p>Abstract</p> <p>Background</p> <p>Extracorporeal lung assist devices are increasingly used in the intensive care unit setting to improve extracorporeal gas exchange mainly in patients with acute respiratory distress syndrome. ARDS is frequently accompanied by acute kidney injury; however it is so far unknown how the combination of these two conditions affects long term survival of critically ill patients.</p> <p>Methods</p> <p>In a retrospective analysis of a tertiary care hospital we evaluated all patients undergoing interventional lung assist (iLA) treatment between January 1^st2005 and December 31^st2009. Data from all 61 patients (31 F/30 M), median age 40 (28 to 52) years were obtained by chart review. Follow up data up to one year were obtained.</p> <p>Results</p> <p>Of the 61 patients undergoing iLA membrane ventilator treatment 21 patients had acute kidney injury network (AKIN) stage 3 and were treated by extended dialysis (ED). Twenty-eight day survival of all patients was 33%. While patients without ED showed a 28 day survival of 40%, the survival of patients with ED was only 19%. Patients on ED were not different in respect to age, weight, Horowitz index and underlying disease.</p> <p>Conclusions</p> <p>AKI requiring ED therapy in patients undergoing iLA treatment increases mortality in ICU patients. Patients in whom iLA was placed as a bridge to lung transplantation and that were successfully transplanted showed the best outcome. Future studies have to clarify whether it is possible to identify patients that truly benefit from the combination of these two extracorporeal treatment methods.</p

Missing value imputation improves clustering and interpretation of gene expression microarray data

<p>Abstract</p> <p>Background</p> <p>Missing values frequently pose problems in gene expression microarray experiments as they can hinder downstream analysis of the datasets. While several missing value imputation approaches are available to the microarray users and new ones are constantly being developed, there is no general consensus on how to choose between the different methods since their performance seems to vary drastically depending on the dataset being used.</p> <p>Results</p> <p>We show that this discrepancy can mostly be attributed to the way in which imputation methods have traditionally been developed and evaluated. By comparing a number of advanced imputation methods on recent microarray datasets, we show that even when there are marked differences in the measurement-level imputation accuracies across the datasets, these differences become negligible when the methods are evaluated in terms of how well they can reproduce the original gene clusters or their biological interpretations. Regardless of the evaluation approach, however, imputation always gave better results than ignoring missing data points or replacing them with zeros or average values, emphasizing the continued importance of using more advanced imputation methods.</p> <p>Conclusion</p> <p>The results demonstrate that, while missing values are still severely complicating microarray data analysis, their impact on the discovery of biologically meaningful gene groups can – up to a certain degree – be reduced by using readily available and relatively fast imputation methods, such as the Bayesian Principal Components Algorithm (BPCA).</p

A role for monoubiquitinated FANCD2 at telomeres in ALT cells

Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize with telomeres or PML bodies in cells which express telomerase. Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear core complex, regulate FANCD2 monoubiquitination and the telomeric localization of FANCD2 in ALT cells. Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomeres in ALT cells but not in telomerase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombination between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability

Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis

Activated T cells require anti-apoptotic cytokines for their survival. The anti-apoptotic effects of these factors are mediated by their influence on the balance of expression and localisation of pro- and anti-apoptotic members of the Bcl-2 family. Among the anti-apoptotic Bcl-2 family members, the expression level of Bcl-2 itself and its interaction with the pro-apoptotic protein Bim are now regarded as crucial for the regulation of survival in activated T cells. We studied the changes in Bcl-2 levels and its subcellular distribution in relation to mitochondrial depolarisation and caspase activation in survival factor deprived T cells. Intriguingly, the total Bcl-2 level appeared to remain stable, even after caspase 3 activation indicated entry into the execution phase of apoptosis. However, cell fractionation experiments showed that while the dominant nuclear pool of Bcl-2 remained stable during apoptosis, the level of the smaller mitochondrial pool was rapidly downregulated. Signals induced by anti-apoptotic cytokines continuously replenish the mitochondrial pool, but nuclear Bcl-2 is independent of such signals. Mitochondrial Bcl-2 is lost rapidly by a caspase independent mechanism in the absence of survival factors, in contrast only a small proportion of the nuclear pool of Bcl-2 is lost during the execution phase and this loss is a caspase dependent process. We conclude that these two intracellular pools of Bcl-2 are regulated through different mechanisms and only the cytokine-mediated regulation of the mitochondrial pool is relevant to the control of the initiation of apoptosis