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

Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity

Quercetin (3,5,7,3′,4′-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3′-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3′-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4′-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Transformation of Human Mesenchymal Cells and Skin Fibroblasts into Hematopoietic Cells

Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs) and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza) and the growth factors (GF) granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy

On the computation of matrices of traces and radicals of ideals

AbstractLet f1,…,fs∈K[x1,…,xm] be a system of polynomials generating a zero-dimensional ideal I, where K is an arbitrary algebraically closed field. We study the computation of “matrices of traces” for the factor algebra A≔K[x1,…,xm]/I, i.e. matrices with entries which are trace functions of the roots of I. Such matrices of traces in turn allow us to compute a system of multiplication matrices {Mxi∣i=1,…,m} of the radical I.We first propose a method using Macaulay type resultant matrices of f1,…,fs and a polynomial J to compute moment matrices, and in particular matrices of traces for A. Here J is a polynomial generalizing the Jacobian. We prove bounds on the degrees needed for the Macaulay matrix in the case when I has finitely many projective roots in PKm. We also extend previous results which work only for the case where A is Gorenstein to the non-Gorenstein case.The second proposed method uses Bezoutian matrices to compute matrices of traces of A. Here we need the assumption that s=m and f1,…,fm define an affine complete intersection. This second method also works if we have higher-dimensional components at infinity. A new explicit description of the generators of I are given in terms of Bezoutians

The Making of Sporting Cultures

The Making of Sporting Cultures presents an analysis of western sport by examining how the collective passions and feelings of people have contributed to the making of sport as a ‘way of life’. The popularity of sport is so pronounced in some cases that we speak of certain sports as ‘national pastimes’. Baseball in the United States, soccer in Britain and cricket in the Caribbean are among the relevant examples discussed. Rather than regarding the historical development of sport as the outcome of passive spectator reception, this work is interested in how sporting cultures have been made and developed over time through the active engagement of its enthusiasts. This is to study the history of sport not only ‘from below’, but also ‘from within’, as a means to understanding the ‘deep relationship’ between sport and people within class contexts – the middle class as well as the working class. Contestation over the making of sport along axes of race, gender and class are discussed where relevant. A range of cultural writers and theorists are examined in regard to both how their writing can help us understand the making of sport and as to how sport might be located within an overall cultural context – in different places and times. The book will appeal to students and academics within humanities disciplines such as cultural studies, history and sociology and to those in sport studies programmes interested in the historical, cultural and social aspects of sport