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

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

The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport.

The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an alpha-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux

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

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

Detection and Understanding of Natural CO2 Releases in KwaZulu-Natal, South Africa

Natural carbon dioxide (CO2) emanates from a number of sites along a N-S trend that coincides with a mapped fault near the village of Bongwana in KwaZulu-Natal, South Africa. In addition to the natural CO2 seeps a groundwater well drilled on a farm in Bongwana encountered CO2 and now leaks. Thus the Bongwana sites provide excellent analogues for failed CO2 storage under the two primary leakage scenarios; 1) abrupt leakage through injection well failure or leakage up an abandoned well, and 2) gradual leakage, through undetected faults, fractures or wells. Here we present results from preliminary fieldwork undertaken in September 2015

An Instrument to Measure Skeletal Burden and Predict Functional Outcome in Fibrous Dysplasia of Bone

Abstract An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. Introduction: Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. Materials and Methods: Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). Results: The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and −0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, −0.42 to −0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. Conclusions: This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome