The continually renewing epithelium of the intestinal tract arises from the visceral endoderm by a series of complex developmental transitions. The mechanisms that establish and maintain the processes of cellular renewal, cell lineage allocation, and tissue restriction and spatial assignment of gene expression in this epithelium are unknown. An understanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these processes. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differentiated enterocytes, is dependent on binding of a tissue-specific homeodomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of the caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodomain gene family, we show that mouse Cdx-2 binds as a dimer to its regulatory element and that dimerization in vitro is dependent on redox potential. These characteristics of the interaction of Cdx-2 with its regulatory element provide for a number of potential mechanisms for transcriptional regulation. Taken together, these findings suggest that members of the Cdx gene family play a fundamental role both in the establishment of the intestinal phenotype during development and in maintenance of this phenotype via transcriptional activation of differentiated intestinal genes.The epithelium of the intestinal tract arises from the visceral endoderm by progression through a series of developmental transitions (reviewed in references 33, 34, and 42). The early signals for intestinal development have been shown to be partially directed by the interaction of mesoderm with endoderm, although the mechanism of this effect has not been elucidated (reviewed in references 23 and 24). Later events include the emergence of different epithelial cell lineages, formation of crypts (proliferative compartment) and villi (differentiated compartment), and the coordinated expression of cell-specific genes. The resultant mature epithelia of the small intestine and colon have marked regional differences in architecture, cell populations, and gene expression which define distinct functional zones of the adult gut (reviewed in references 20, 21, and 50). These region-specific phenotypes are maintained throughout the life of the animal. The regulatory mechanisms that orchestrate these complex developmental transitions and maintain the well-ordered regional phenotypes along the cephalocaudal and crypt-villus axes have not been defined.

ASO treatment alone has no effect, it can sensitize myeloma cell lines to dexamethasone (Dex), whereas Bcl-x L ASO in combination with Dex still had no effect. As MM remains an incurable disease despite intensive chemotherapy, these results suggest that Mcl-1 antisense strategy rather than Bcl-2 antisense strategy could be of considerable importance in the treatment of MM. (Blood. 2002;100:194-199)

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Resistance to apoptosis, which plays an important role in tumors that are refractory to chemotherapy, is regulated by the ratio of antiapoptotic to proapoptotic proteins. By manipulating levels of these proteins, cells can become sensitized to undergo apoptosis in response to chemotherapeutic agents. Alternative splicing of the bcl-x gene gives rise to two proteins with antagonistic functions: Bcl-xL, a well-characterized antiapoptotic protein, and Bcl-xS, a proapoptotic protein. We show here that altering the ratio of Bcl-xL to Bcl-xS in the cell using an antisense oligonucleotide permitted cells to be sensitized to undergo apoptosis in response to ultraviolet B radiation and chemotherapeutic drug treatment. These results demonstrate the ability of a chemically modified oligonucleotide to alter splice site selection in an endogenous gene and illustrate a powerful tool to regulate cell survival.

OBJECTIVE:To assess whether Medicare fee-forservice beneficiaries with depression and diabetes had a higher mortality rate over a 2-year period compared with beneficiaries with diabetes alone. DESIGN: Evidence of depression was based on a physician diagnosis or self-reported prescription of an antidepressant in the year prior to screening, or a score of ≥3 on the Patient Health Questionnaire two-item questionnaire. Mortality was assessed bi-monthly by checking Medicare claims and eligibility files or from information from telephone contact with the participant's family. Cox proportional hazard regression models were used to calculate adjusted hazard ratios of death in depressed versus nondepressed beneficiaries with diabetes.PARTICIPANTS: A total of 10,704 beneficiaries with diabetes enrolled in a disease management program were surveyed with a health assessment questionnaire and followed over a two-year period. MAIN RESULTS:Comorbid depression in Medicare beneficiaries with diabetes participating in a disease management program was associated with an increased risk for all-cause mortality over a two-year period of approximately 36% to 38%, depending on the definition of depression that was used. No significant increase in rates of cause-specific mortality from macrovascular disease were found in depressed versus nondepressed beneficiaries. CONCLUSION:Among a large Medicare cohort of feefor-service beneficiaries with diabetes, comorbid depression was associated with an increase in all-cause mortality over a two-year period. Future research will be required to determine whether the increase in mortality associated with depression is due to potential behavioral mediators (i.e., smoking, poor adherence to diet) or physiologic abnormalities (i.e., hypothalamic-pituitary axis dysregulation) associated with depression.