1,612 research outputs found
Combination of IFNα and poly-I: C reprograms bladder cancer microenvironment for enhanced CTL attraction
Background: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8+ T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs.Methods: Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data.Results: Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage.Conclusions: The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases
The Hawking-Page crossover in noncommutative anti-deSitter space
We study the problem of a Schwarzschild-anti-deSitter black hole in a
noncommutative geometry framework, thought to be an effective description of
quantum-gravitational spacetime. As a first step we derive the noncommutative
geometry inspired Schwarzschild-anti-deSitter solution. After studying the
horizon structure, we find that the curvature singularity is smeared out by the
noncommutative fluctuations. On the thermodynamics side, we show that the black
hole temperature, instead of a divergent behavior at small scales, admits a
maximum value. This fact implies an extension of the Hawking-Page transition
into a van der Waals-like phase diagram, with a critical point at a critical
cosmological constant size in Plank units and a smooth crossover thereafter. We
speculate that, in the gauge-string dictionary, this corresponds to the
confinement "critical point" in number of colors at finite number of flavors, a
highly non-trivial parameter that can be determined through lattice
simulations.Comment: 24 pages, 6 figure, 1 table, version matching that published on JHE
Minimum length effects in black hole physics
We review the main consequences of the possible existence of a minimum
measurable length, of the order of the Planck scale, on quantum effects
occurring in black hole physics. In particular, we focus on the ensuing minimum
mass for black holes and how modified dispersion relations affect the Hawking
decay, both in four space-time dimensions and in models with extra spatial
dimensions. In the latter case, we briefly discuss possible phenomenological
signatures.Comment: 29 pages, 12 figures. To be published in "Quantum Aspects of Black
Holes", ed. X. Calmet (Springer, 2014
Hawking emission from quantum gravity black holes
We address the issue of modelling quantum gravity effects in the evaporation
of higher dimensional black holes in order to go beyond the usual
semi-classical approximation. After reviewing the existing six families of
quantum gravity corrected black hole geometries, we focus our work on
non-commutative geometry inspired black holes, which encode model independent
characteristics, are unaffected by the quantum back reaction and have an
analytical form compact enough for numerical simulations. We consider the
higher dimensional, spherically symmetric case and we proceed with a complete
analysis of the brane/bulk emission for scalar fields. The key feature which
makes the evaporation of non-commutative black holes so peculiar is the
possibility of having a maximum temperature. Contrary to what happens with
classical Schwarzschild black holes, the emission is dominated by low frequency
field modes on the brane. This is a distinctive and potentially testable
signature which might disclose further features about the nature of quantum
gravity.Comment: 36 pages, 18 figures, v2: updated reference list, minor corrections,
version matching that published on JHE
Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin
Metastasis is a multi-step process wherein tumour cells detach from the primary mass, migrate through barrier matrices, gain access to conduits to disseminate, and subsequently survive and proliferate in an ectopic site. During the initial invasion stage, prostate carcinoma cells undergo epithelial–mesenchymal-like transition with gain of autocrine signalling and loss of E-cadherin, hallmarks that appear to enable invasion and dissemination. However, some metastases express E-cadherin, and we found close connections between prostate carcinoma cells and hepatocytes in a liver microtissue bioreactor. We hypothesise that phenotypic plasticity occurs late in prostate cancer progression at the site of ectopic seeding. Immunofluorescence staining for E-cadherin in co-cultures of hepatocytes and DU-145 prostate cancer cells revealed E-cadherin upregulation at peripheral sites of contact by day 2 of co-culture; E-cadherin expression also increased in PC-3 cells in co-culture. These carcinoma cells bound to hepatocytes in an E-cadherin-dependent manner. Although the signals by which the hepatocytes elicited E-cadherin expression remain undetermined, it appeared related to downregulation of epidermal growth factor receptor (EGFR) signalling. Inhibition of autocrine EGFR signalling increased E-cadherin expression and cell–cell heterotypic adhesion; further, expression of a downregulation-resistant EGFR variant prevented E-cadherin upregulation. These findings were supported by finding E-cadherin and catenins but not activated EGFR in human prostate metastases to the liver. We conclude that the term epithelial–mesenchymal transition only summarises the transient downregulation of E-cadherin for invasion with re-expression of E-cadherin being a physiological consequence of metastatic seeding
A Measurement of Rb using a Double Tagging Method
The fraction of Z to bbbar events in hadronic Z decays has been measured by
the OPAL experiment using the data collected at LEP between 1992 and 1995. The
Z to bbbar decays were tagged using displaced secondary vertices, and high
momentum electrons and muons. Systematic uncertainties were reduced by
measuring the b-tagging efficiency using a double tagging technique. Efficiency
correlations between opposite hemispheres of an event are small, and are well
understood through comparisons between real and simulated data samples. A value
of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is
statistical and the second systematic. The uncertainty on Rc, the fraction of Z
to ccbar events in hadronic Z decays, is not included in the errors. The
dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the
deviation of Rc from the value 0.172 predicted by the Standard Model. The
result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the
Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European
Physical Journal
Measurement of the B+ and B-0 lifetimes and search for CP(T) violation using reconstructed secondary vertices
The lifetimes of the B+ and B-0 mesons, and their ratio, have been measured in the OPAL experiment using 2.4 million hadronic Z(0) decays recorded at LEP. Z(0) --> b (b) over bar decays were tagged using displaced secondary vertices and high momentum electrons and muons. The lifetimes were then measured using well-reconstructed charged and neutral secondary vertices selected in this tagged data sample. The results aretau(B+) = 1.643 +/- 0.037 +/- 0.025 pstau(Bo) = 1.523 +/- 0.057 +/- 0.053 pstau(B+)/tau(Bo) = 1.079 +/- 0.064 +/- 0.041,where in each case the first error is statistical and the second systematic.A larger data sample of 3.1 million hadronic Z(o) decays has been used to search for CP and CPT violating effects by comparison of inclusive b and (b) over bar hadron decays, No evidence fur such effects is seen. The CP violation parameter Re(epsilon(B)) is measured to be Re(epsilon(B)) = 0.001 +/- 0.014 +/- 0.003and the fractional difference between b and (b) over bar hadron lifetimes is measured to(Delta tau/tau)(b) = tau(b hadron) - tau((b) over bar hadron)/tau(average) = -0.001 +/- 0.012 +/- 0.008
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