The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent

Flavour SU(3) Symmetry in Charmless B Decays

QCD sum rules are used to estimate the flavour SU(3)-symmetry violation in two-body B decays to pions and kaons. In the factorizable amplitudes the SU(3)-violation manifests itself in the ratio of the decay constants f_K/f_pi and in the differences between the B->K, B_s->K and B->pi form factors. These effects are calculated from the QCD two-point and light-cone sum rules, respectively, in terms of the strange quark mass and the ratio of the strange and nonstrange quark-condensate densities. Importantly, QCD sum rules predict that SU(3) breaking in the heavy-to-light form factors can be substantial and does not vanish in the heavy-quark mass limit. Furthermore, we investigate the strange-quark mass dependence of nonfactorizable effects in the B->K pi decay amplitudes. Taking into account these effects we estimate the accuracy of several SU(3)-symmetry relations between charmless B-decay amplitudes.Comment: Two references added, version to be published in Phys.Rev.D, 21 pages, 12 postscript figure

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma.

The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood

Is there still any Tc mystery in lattice QCD? Results with physical masses in the continuum limit III

The present paper concludes our investigations on the QCD cross-over transition temperatures with 2+1 staggered flavours and one-link stout improvement. We extend our previous two studies [Phys. Lett. B643 (2006) 46, JHEP 0906:088 (2009)] by choosing even finer lattices ($N_t$=16) and we work again with physical quark masses. The new results on this broad cross-over are in complete agreement with our earlier ones. We compare our findings with the published results of the hotQCD collaboration. All these results are confronted with the predictions of the Hadron Resonance Gas model and Chiral Perturbation Theory for temperatures below the transition region. Our results can be reproduced by using the physical spectrum in these analytic calculations. The findings of the hotQCD collaboration can be recovered by using a distorted spectrum which takes into account lattice discretization artifacts and heavier than physical quark masses. This analysis provides a simple explanation for the observed discrepancy in the transition temperatures between our and the hotQCD collaborations.Comment: 25 pages, 10 figures and 3 table

Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models.

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic

Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma

Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma

QCD Short-distance Constraints and Hadronic Approximations

This paper discusses a general class of ladder resummation inspired hadronic approximations. It is found that this approach naturally reproduces many successes of single meson per channel saturation models (e.g. VMD) and NJL based models. In particular the existence of a constituent quark mass and a gap equation follows naturally. We construct an approximation that satisfies a large set of QCD short-distance and large $N_c$ constraints and reproduces many hadronic observables. We show how there exists in general a problem between QCD short-distance constraints for Green Functions and those for form factors and cross-sections following from the quark-counting rule. This problem while expected for Green functions that do not vanish in purely perturbative QCD also persists for many Green functions that are order parameters.Comment: 27 page

1S and MSbar Bottom Quark Masses from Upsilon Sum Rules

The bottom quark 1S mass, $M_b^{1S}$, is determined using sum rules which relate the masses and the electronic decay widths of the $\Upsilon$ mesons to moments of the vacuum polarization function. The 1S mass is defined as half the perturbative mass of a fictitious ${}^3S_1$ bottom-antibottom quark bound state, and is free of the ambiguity of order $\Lambda_{QCD}$ which plagues the pole mass definition. Compared to an earlier analysis by the same author, which had been carried out in the pole mass scheme, the 1S mass scheme leads to a much better behaved perturbative series of the moments, smaller uncertainties in the mass extraction and to a reduced correlation of the mass and the strong coupling. We arrive at $M_b^{1S}=4.71\pm 0.03$ GeV taking $\alpha_s(M_Z)=0.118\pm 0.004$ as an input. From that we determine the $\bar{MS}$ mass as $\bar m_b(\bar m_b) = 4.20 \pm 0.06$ GeV. The error in $\bar m_b(\bar m_b)$ can be reduced if the three-loop corrections to the relation of pole and $\bar{MS}$ mass are known and if the error in the strong coupling is decreased.Comment: 20 pages, latex; numbers in Tabs. 2,3,4 corrected, a reference and a comment on the fitting procedure added, typos in Eqs. 2 and 23 eliminate