Concentration-dependent half-lives of polychlorinated biphenyl in sera from an occupational cohort.

Polychlorinated biphenyls (PCBs) are carcinogenic. Estimating PCB half-life in the body based on levels in sera from exposed workers is complicated by the fact that occupational exposure to PCBs was to commercial PCB products (such as Aroclors 1242 and 1254) comprised of varying mixtures of PCB congeners. Half-lives were estimated using sera donated by 191 capacitor manufacturing plant workers in 1976 during PCB use (1946-1977), and post-exposure (1979, 1983, and 1988). Our aims were to: (1) determine the role of covariates such as gender on the half-life estimates, and (2) compare our results with other published half-life estimates based on exposed workers. All serum PCB levels were adjusted for PCB background levels. A linear spline model with a single knot was used to estimate two separate linear equations for the first two serum draws (Equation A) and the latter two (Equation B). Equation A gave half-life estimates of 1.74 years and 6.01 years for Aroclor 1242 and Aroclor 1254, respectively. Estimates were 21.83 years for Aroclor 1242 and 133.33 years for Aroclor 1254 using Equation B. High initial body burden was associated with rapid PCB elimination in workers at or shortly after the time they were occupationally exposed and slowed down considerably when the dose reached background PCB levels. These concentration-dependent half-life estimates had a transition point of 138.57 and 34.78 ppb for Aroclor 1242 and 1254, respectively. This result will help in understanding the toxicological and epidemiological impact of exposure to PCBs in humans.

The anti-lymphoma activity of APO866, an inhibitor of nicotinamide adenine dinucleotide biosynthesis, is potentialized when used in combination with anti-CD20 antibody.

Abstract APO866 is an inhibitor of nicotinamide adenine dinucleotide (NAD) biosynthesis that exhibits potent anti-lymphoma activity. Rituximab (RTX), an anti-CD20 antibody, kills lymphoma cells by direct apoptosis and antibody- and complement-dependent cell-mediated cytotoxicities, and has clinical efficacy in non-Hodgkin cell lymphomas. In the present study, we evaluated whether RTX could potentiate APO866-induced human B-lymphoma cell death and shed light on death-mediated mechanisms associated with this drug combination. We found that RTX significantly increases APO866-induced death in lymphoma cells from patients and lines. Mechanisms include enhancement of autophagy-mediated cell death, activation of caspase 3 and exacerbation of mitochondrial depolarization, but not increase of reactive oxygen species (ROS) production, when compared with those induced by each drug alone. In vivo, combined administration of APO866 with RTX in a laboratory model of human aggressive lymphoma significantly decreased tumor burden and prolonged survival over single-agent treatment. Our study demonstrates that the combination of RTX and APO866 optimizes B-cell lymphoma apoptosis and therapeutic efficacy over both compounds administered separately.

Isolation and characterization of carcinoembryonic antigen (CEA) extracted from normal human colon mucosa.

Carcinoembryonic antigen (CEA) was identified in perchloric acid (PCA)_extract from normal colon mucosa by 2 immunological criteria: a line of identity in double diffusion and a parallel inhibition curve in radioimmunoassay (RIA), both with reference colon carcinoma-CEA (CEA-Tu). The average concentration of CEA in normal colon mucosa (CEA-No) was 35 times lower than in primary large bowel carcinomas and 230 times lower than in metastatic colon or rectum carcinomas. CEA-No was purified from PCA extracts of normal colon mucosa by Sephadex G-200 filtration and immunoadsorbent columns. Purified CEA-No had quatitatively the same inhibition activity in RIA as the British Standard CEA coded 73/601. Purified CEA-No was labelled with 125I. The percentage of binding of labelled CEA-No to a specific goat anti-CEA-Tu antiserum was similar to that of CEA-Tu. Labelled CEA-No could be used as radioactive tracer in RIA as well as labelled CEA-Tu. The physico-chemical properties of purified CEA-Tu as demonstrated by Sepharose 6 B filtration, SDS Polyacrylamide gel analysis and cesium chloride density gradient, were found to be almost identical to those of reference CEA-Tu. Preliminary results showed that CEA-No and CEA-Tu contained the same types of carbohydrates in similar proportions. A rabbit antiserum against CEA-No was obtained which demonstrated the same specificity as conventional anti-CEA-Tu antisera.