531 research outputs found
Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study
Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud
\ud
Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud
\ud
Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud
\ud
Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising
Recommended from our members
Experiment on mass-stripping of interstellar cloud following shock passage
The interaction of supernova shocks and interstellar clouds is an important astrophysical phenomenon which can lead to mass-stripping (transfer of material from cloud to surrounding flow, ''mass-loading'' the flow) and possibly increase the compression in the cloud to high enough densities to trigger star formation. Our experiments attempt to simulate and quantify the mass-stripping as it occurs when a shock passes through interstellar clouds. We drive a strong shock using 5 kJ of the 30 kJ Omega laser into a cylinder filled with low-density foam with an embedded 120 {micro}m Al sphere simulating an interstellar cloud. The density ratio between Al and foam is {approx} 9. Time-resolved x-ray radiographs show the cloud getting compressed by the shock (t {approx} 5 ns), undergoing a classical Kelvin-Helmholtz roll-up (12 ns) followed by a Widnall instability (30 ns), an inherently 3d effect that breaks the 2d symmetry of the experiment. Material is continuously being stripped from the cloud at a rate which is shown to be inconsistent with laminar models for mass-stripping (the cloud is fully stripped by 80 ns-100 ns, ten times faster than the laminar model). We present a new model for turbulent mass-stripping that agrees with the observed rate and which should scale to astrophysical conditions, which occur at even higher Reynolds numbers than the current experiment. The new model combines the integral momentum equations, potential flow past a sphere, flat plate skin friction coefficients, and Spalding's law of the wall for turbulent boundary layers
Recommended from our members
Mass-stripping analysis of an interstellar cloud by a supernova shock
The interaction of supernova shocks and interstellar clouds is an important astrophysical phenomenon since it can result in stellar and planetary formation. Our experiments attempt to simulate this mass-loading as it occurs when a shock passes through interstellar clouds. We drive a strong shock using the Omega laser ({approx} 5 kJ) into a foam-filled cylinder with an embedded Al sphere (diameter D = 120 {micro}m) simulating an interstellar cloud. The density ratio between Al and foam is {approx}9. We have previously reported on the interaction between shock and cloud, the ensuing Kelvin-Helmholtz and Widnall instabilities, and the rapid stripping of all mass from the cloud. We now present a theory that explains the rapid mass-stripping. The theory combines (1) the integral momentum equations for a viscous boundary layer, (2) the equations for a potential flow past a sphere, (3) Spalding's law of the wall for turbulent boundary layers, and (4) the skin friction coefficient for a turbulent boundary layer on a flat plate. The theory gives as its final result the mass stripped from a sphere in a turbulent high Reynolds number flow, and it agrees very well with our experimental observations
Changes in gene expression in human skeletal stem cells transduced with constitutively active Gs\u3b1 correlates with hallmark histopathological changes seen in fibrous dysplastic bone
Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the \u3b1 subunit of the G protein-coupled receptor complex (Gs\u3b1). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (Gs\u3b1R201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the Gs\u3b1R201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets
Notch signaling during human T cell development
Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse
On Validating an Astrophysical Simulation Code
We present a case study of validating an astrophysical simulation code. Our
study focuses on validating FLASH, a parallel, adaptive-mesh hydrodynamics code
for studying the compressible, reactive flows found in many astrophysical
environments. We describe the astrophysics problems of interest and the
challenges associated with simulating these problems. We describe methodology
and discuss solutions to difficulties encountered in verification and
validation. We describe verification tests regularly administered to the code,
present the results of new verification tests, and outline a method for testing
general equations of state. We present the results of two validation tests in
which we compared simulations to experimental data. The first is of a
laser-driven shock propagating through a multi-layer target, a configuration
subject to both Rayleigh-Taylor and Richtmyer-Meshkov instabilities. The second
test is a classic Rayleigh-Taylor instability, where a heavy fluid is supported
against the force of gravity by a light fluid. Our simulations of the
multi-layer target experiments showed good agreement with the experimental
results, but our simulations of the Rayleigh-Taylor instability did not agree
well with the experimental results. We discuss our findings and present results
of additional simulations undertaken to further investigate the Rayleigh-Taylor
instability.Comment: 76 pages, 26 figures (3 color), Accepted for publication in the ApJ
The molybdenum isotopic composition of the modern ocean
Natural variations in the isotopic composition of molybdenum (Mo) are showing increasing potential as a tool in geochemistry. Although the ocean is an important reservoir of Mo, data on the isotopic composition of Mo in seawater are scarce. We have recently developed a new method for the precise determination of Mo isotope ratios on the basis of preconcentration using a chelating resin and measurement by multiple-collector inductively coupled plasma mass spectrometry (MC-ICP-MS), which allows us to measure every stable Mo isotope. In this study, 172 seawater samples obtained from 9 stations in the Pacific, Atlantic, and Southern Oceans were analyzed, giving global coverage and the first full depth-profiles. The average isotope composition in δA/95Mo (relative to a Johnson Matthey Mo standard solution) was as follows: δ92/95Mo = –2.54 ± 0.16‰ (2SD), δ94/95Mo = –0.73 ± 0.19‰, δ96/95Mo = 0.85 ± 0.07‰, δ97/95Mo = 1.68 ± 0.08‰, δ98/95Mo = 2.48 ± 0.10‰, and δ100/95Mo = 4.07 ± 0.18‰. The δ values showed an excellent linear correlation with atomic mass of AMo (R2 = 0.999). Three-isotope plots for the Mo isotopes were fitted with straight lines whose slopes agreed with theoretical values for mass-dependent isotope fractionation. These results demonstrate that Mo isotopes are both uniformly distributed and follow a mass-dependent fractionation law in the modern oxic ocean. A common Mo standard is urgently required for the precise comparison of Mo isotopic compositions measured in different laboratories. On the other hand, our results strongly support the possibility of seawater as an international reference material for Mo isotopic composition
Orbital Physics in the Perovskite Ti Oxides
In the perovskite Ti oxide RTiO3 (R=rare-earth ions), the Ti t2g orbitals and
spins in the 3d^1 state couple each other through the strong electron
correlations, resulting in a rich variety of orbital-spin phases. The origin
and nature of orbital-spin states of these Mott insulators have been
intensively studied. In this article, we review the studies on orbital physics
in the perovskite titanates. We focus on the following three topics: (1) the
origin and nature of the ferromagnetism as well as the orbital ordering in the
compounds with relatively small R ions such as GdTiO3 and YTiO3, (2) the origin
of the G-type antiferromagnetism and the orbital state in LaTiO3, and (3) the
orbital-spin structures in other AFM(G) compounds with relatively large R ions
(R=Ce, Pr, Nd and Sm). On the basis of these discussions, we discuss the whole
phase diagram together with mechanisms of the magnetic phase transition. We
also show that the Ti t2g degeneracy is inherently lifted in the titanates,
which allows the single-band descriptions of the ground-state and low-energy
electronic structures as a good starting point. Our analyses indicate that
these compounds offer touchstone materials described by the single-band Hubbard
model on the cubic lattice. From this insight, we also reanalyze the hole-doped
titanates. Experimentally revealed filling-dependent and bandwidth-dependent
properties and the critical behavior of the metal-insulator transitions are
discussed in the light of theories based on the single-band Hubbard models.Comment: Review article, 26 pages, to appear in New Journal of Physic
Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer
The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker
- …