Kaiser Permanente

Being able to conduct a simple blood test to predict probable cancer development later in life is of great use to physicians. In collaboration with Kaiser Permanente Division of Research (KPDOR) and International Agency for Research on Cancer, and others, we are currently examining the association of organochlorides, aflatoxin, and hepatitis C with the subsequent development of liver cancer. Incorporating the latest techniques in proteomics research, we seek to determine a connection between serum proteins and subsequent development of breast cancer in collaboration KPDOR and Albert Einstein College of Medicine.

OFAS has a long history of studying Non-Hodgkin’s Lymphoma with KPDOR. Building on past findings, we are undertaking the analysis of a variety of organochlorine levels, Epstein-Barr Virus seropositivity, and cytokine and immunological biomarkers. This project is composed of two studies, taking place in parallel, with samples from the Northern California Region Kaiser Permanente Medical Care Program being analyzed at three separate laboratories: Centers for Disease Control and PreventionNational Institutes of Health, and Virolab.

Heart Disease
We are working with both Kaiser Permanente and Aviir on an investigation into heart disease. Half of sudden cardiac mortality occurs in patients with no previous diagnosis of cardiovascular disease. A simple blood test that accurately measures inflammatory protein markers in serum has been developed. It uses a multiplexed ELISA technique to measure 45 biomarkers from previously frozen serum. Subjects in the study were healthy participants in the Kaiser Permanente Multiphasic Health Checkup from whom serum was obtained and frozen between 1985 and 1991. This study demonstrated the feasibility and utility of a multiplexed proteomic based algorithm for the prediction of Acute Myocardial Infarction.

Oxford University
A Norwegian study on human subjects revealed a direct correlation between total plasma cysteine levels and adiposity. Because cysteine is a metabolite derived from methionine, we conducted collaborative work with Dr. Helga Refsum at Oxford University to examine whether there was a correlation between total serum cysteine and body composition in methionine-restricted (MR) rats. MR reduced total cysteine levels in rats, correlating with reduced adiposity in these animals. Furthermore, the addition of cysteine to the MR diet reversed MR’s effects on fat mass, providing strong evidence that adiposity is controlled by blood levels of cysteine.

Pennington Biomedical Research Center
OFAS has demonstrated that methionine-restricted (MR) rats live on average 40% longer than their control-fed (CF) counterparts. Interestingly, these animals also have lower body weight and limited fat accumulations despite higher calorie intake per gram of body weight than CF animals. Our observations suggested that MR rats resist fat deposition because they are able to convert excess calories to heat (increased energy expenditure). In collaboration with Pennington Biomedical Research Center, OFAS found that 24-hour energy expenditure was increased in young, adult, and old MR rats. This effect was more pronounced during the “dark cycle” when rodents are more active. Activity of older CF and MR animals was found to be similar, ruling out activity as an explanation for higher energy expenditure. Our data also indicates that MR animals utilize fuel substrates differently and that specific genes associated with energy expenditure are increased relative to CF animals.

Having shown the effectiveness of the MR diet in rodents, we chose to examine its effects in humans. We conducted a Phase I Clinical Trial with Pennington using MR in obese human adults meeting the Adult Treatment Panel III (ATP III) criteria for Metabolic Syndrome. The objective of the study was to determine whether the MR diet could reduce weight and thus improve insulin resistance in these subjects. This double-blind, placebo-control study assigned subjects to 16 weeks of either the MR diet, containing 2 mg/kg/day methionine, or a control diet, containing 35 mg/kg/day methionine. Insulin sensitivity, body fat mass, and serum analytes, as well as weight and energy expenditure, were among the parameters used to monitor MR-induced changes.