Carol Bernstein

Crypt-restricted loss and decreased protein expression of cytochrome C oxidase subunit I as potential hypothesis-driven biomarkers of colon cancer risk.

There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects ∼50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02). It should be noted that a defect in cytochrome c oxidase subunit I immunostaining was not detected in all biopsy samples from each patient for whom some abnormality was found, indicating a “patchiness” in the cytochrome c oxidase subunit I field defect. As a result of this “patchiness,” the increased variability in the incidence of crypt-restricted loss of cytochrome c oxidase subunit I expression was a statistically significant feature of the neoplasia group. Crypt-restricted loss of cytochrome c oxidase subunit I has not been previously reported in colonic mucosa and is presumably the result of a crypt-restricted stem cell mutation. Decreased cytochrome c oxidase subunit I expression also significantly correlated with apoptosis resistance, a factor known to contribute to carcinogenesis. The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk.

Evolutionary Origin and Adaptive Function of Meiosis

The origin of meiosis and its adaptive function in eukaryotes, and the related problem of the origin and adaptive function of sex in eukaryotes, are fundamental issues in biology. Among eukaryotes, meiosis and sexual reproduction are widespread, occurring in single-celled eukaryotes (including protozoans such as paramecium), and fungi (e.g. yeast) and in most multicellular organisms including animals and most plants. Accumulating evidence indicates that meiosis arose very early in the evolution of eukaryotes (reviewed in Bernstein & Bernstein, 2010). Thus, basic features of meiosis were likely already present in the prokaryotic ancestors of eukaryotes.

DNA Repair in Bacteriophage

Starting with the very first studies on DNA repair in 1947, most of the earliest work, involving recombinational repair, photoreactivation, and excision repair, were carried out with bacteriophage (phage) T4 (reviewed in 4,6). Repair processes in phage appear to be similar to DNA repair processes in other organsims, and genes necessary for DNA repair in phage, such as phage T4 genes denV and uvsX, are homologous to repair genes in bacteria and eucaryotes (see Sub heading 7.). Thus, study of DNA repair processes in phage illuminates the mechanisms and adaptive functions of similar, but often more complex, processes in bacteria and eucaryotes.

Chapter 3:Bile-Acid Induction of Apoptosis in Relation to Gastrointestinal Cancer

Apoptosis is a physiological mode of cell death involving an orchestrated series of biochemical events. Apoptosis (from Greek apo -, ptosis-falling) is the normal cellular mechanism through which aged or damaged cells are eliminated from the body. The morphological changes defining apoptosis include...