Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI.

Purpose: A practical, noninvasive method is needed to measure the extracellular pH (pHe) within in vivo tumors to longitudinally monitor tumor acidosis. We have optimized a biomedical imaging method, termed acidoCEST MRI, to provide noninvasive assessments of tumor pHe in preclinical models of mammary carcinoma.

Methods: A CEST-FISP MRI method was optimized to detect the chemical exchange saturation transfer (CEST) of two amide protons of a clinically approved CT contrast agent, iopromide.

Investigating mechanisms of alkalinization for reducing primary breast tumor invasion.

The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate.

Multimodality pH imaging in a mouse dorsal skin fold window chamber model.

Upregulate levels of expression and activity of membrane H ion pumps in cancer cells drives the extracellular pH (pH,) to values lower than normal. Furthermore, disregulated pH is indicative of the changes in glycolytic metabolism in tumor cells and has been shown to facilitate extracellular tissue remodeling during metastasis Therefore, measurement of pH could be a useful cancer biomarker for diagnostic and therapy monitoring evaluation. Multimodality in-vivo imaging of pH in tumorous tissue in a mouse dorsal skin fold window chamber (DSFWC) model is described.

Examining the relationship between diet-induced acidosis and cancer.

Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis.

Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer.

Background: The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer.

A mathematical model of tumour and blood pHe regulation: The HCO3-/CO2 buffering system.

Malignant tumours are characterised by a low, acidic extracellular pH (pHe) which facilitates invasion and metastasis. Previous research has proposed the potential benefits of manipulating systemic pHe, and recent experiments have highlighted the potential for buffer therapy to raise tumour pHe, prevent metastases, and prolong survival in laboratory mice. To examine the physiological regulation of tumour buffering and investigate how perturbations of the buffering system (via metabolic/respiratory disorders or changes in parameters) can alter tumour and blood pHe, we develop a simple compartmentalised ordinary differential equation model of pHe regulation by the HCO3-/CO2 buffering system.

Bicarbonate increases tumor pH and inhibits spontaneous metastases.

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases.

Regulation of the Warburg effect in early-passage breast cancer cells.

Malignancy in cancer is associated with aerobic glycolysis (Warburg effect) evidenced by increased trapping of [(18)F]deoxyglucose (FdG) in patients imaged by positron emission tomography (PET). [(18)F]deoxyglucose uptake correlates with glucose transporter (GLUT-1) expression, which can be regulated by hypoxia-inducible factor 1 alpha (HIF-1alpha). We have previously reported in established breast lines that HIF-1alpha levels in the presence of oxygen leads to the Warburg effect.

Natural and autoantibodies to human T-cell receptor Vbeta segments: potential roles in immunomodulation.

Although the manifestation of inflammatory autodestructive disease is the result of major immunological dysfunction, recent evidence indicates that the immune system attempts to compensate by the production of immunomodulatory autoantibodies. Healthy humans have low levels of naturally occurring autoantibodies directed against the first complementarity-determining region (CDR1) and third framework region (FR3) of their own T-cell receptor (TCR) Vbeta segments, but individuals suffering from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) can have highly elevated levels of these autoantibodies. We cloned and characterized human anti-TCR monoclonal autoantibodies (mAAbs) from RA and SLE patients.

Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo.

The hypoxia-inducible transcription factor (HIF-1alpha) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF-1alpha in experimental tumors. The purpose of this study was to identify MRS-visible metabolic biomarkers for PX-478 response prior to phase I/II clinical trials.

Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors.

Metastatic tumors generally exhibit aerobic glycolysis (the Warburg effect). The advent of [18F]fluorodeoxyglucose positron emission tomography imaging, coupled with recent findings linking hypoxia-inducible factor (HIF-1alpha) overexpression to aggressive cancers, has rekindled an interest in this aspect of tumor metabolism. These studies explore the role of HIF-1alpha in human breast cancer lines and its relationship to glycolytic regulation.

Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice.

The wide diversity of the T and B Ag receptor repertoires becomes even more extensive postneonatally due to the activity of TdT, which adds nontemplated N nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition, complementarity-determining region 3 sequences formed in the absence of TdT are more uniform due to the use of short sequence homologies between the V, D, and J genes. Thus, the action of TdT produces an adult repertoire that is both different from, and much larger than, the repertoire of the neonate.

Human monoclonal natural autoantibodies against the T-cell receptor inhibit interleukin-2 production in murine T cells.

Natural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vbeta TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs)--OR2, OR5 and Syn 2H-11--with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.

Specificity mapping of human anti-T cell receptor monoclonal natural antibodies: defining the properties of epitope recognition promiscuity.

The classical concept of antibody binding is defined as an exclusive and high-affinity interaction with one epitope. The emerging reality about antibody combing sites, however, is that some can bind unrelated determinants. The studies presented here define this quality as epitope recognition promiscuity by analyzing the capacity of monoclonal human autoantibodies to bind sets of overlapping peptides duplicating the complete structures of T cell receptor (TCR) alpha and beta chains and immunoglobulin lambda chain.