OBJECTIVE. Cognitive impairment among the elderly has been linked to mortality in studies of clinical populations. The purpose of this study was to examine the mortality risk associated with cognitive impairment among elderly populations in the community. METHODS. Cognitive impairment and other social and health factors were assessed in 1855 elderly community residents. This sample was reinterviewed periodically to assess changes in health and survival. RESULTS. At baseline 33% of the sample were mildly impaired and 8% were severely impaired. Across a 48-month observation period the survival probability was .85 for the cognitively unimpaired, .69 for the mildly impaired, and .51 for severely impaired respondents. When adjustments were made for the effects of other health and social covariates, severely impaired persons were twice as likely to die as unimpaired persons. Those who were mildly impaired were also at an increased risk. CONCLUSIONS. Other investigators have found that cognitive impairment is a significant predictor of dementia. We found that it is a significant predictor of mortality as well. Early detection of impaired cognition and attention to associated health problems could improve the quality of life of these older adults and perhaps extend their survival.

Recent studies have demonstrated that aldo-keto reductase family 1 B10 (AKR1B10), a novel protein overexpressed in human hepatocellular carcinoma and non-small cell lung carcinoma, may facilitate cancer cell growth by detoxifying intracellular reactive carbonyls. This study presents a novel function of AKR1B10 in tumorigenic mammary epithelial cells (RAO-3), regulating fatty acid synthesis. In RAO-3 cells, Sephacryl-S 300 gel filtration and DEAE-Sepharose ion exchange chromatography demonstrated that AKR1B10 exists in two distinct forms, monomers (ϳ40 kDa) bound to DEAE-Sepharose column and protein complexes (ϳ300 kDa) remaining in flow-through. Co-immunoprecipitation with AKR1B10 antibody and protein mass spectrometry analysis identified that AKR1B10 associates with acetyl-CoA carboxylase-␣ (ACCA), a rate-limiting enzyme of de novo fatty acid synthesis. This association between AKR1B10 and ACCA proteins was further confirmed by co-immunoprecipitation with ACCA antibody and pulldown assays with recombinant AKR1B10 protein. Intracellular fluorescent studies showed that AKR1B10 and ACCA proteins colocalize in the cytoplasm of RAO-3 cells. More interestingly, small interfering RNA-mediated AKR1B10 knock down increased ACCA degradation through ubiquitination-proteasome pathway and resulted in >50% decrease of fatty acid synthesis in RAO-3 cells. These data suggest that AKR1B10 is a novel regulator of the biosynthesis of fatty acid, an essential component of the cell membrane, in breast cancer cells.Aldo-keto reductase family 1 B10 (AKR1B10, 2 also designated aldose reductase-like-1, ARL-1) is a novel protein identified from human hepatocellular carcinoma (1). This protein belongs to the aldo-keto reductase superfamily, a group of proteins implicated in intracellular detoxification, cell carcinogenesis, and cancer therapeutics (2-5). AKR1B10 is primarily expressed in the colon and small intestine with low levels in the liver, thymus, prostate, and testis (1). However, this gene is overexpressed in 54% of human hepatocellular carcinoma, 84.4% of lung squamous cell carcinoma, and 29.2% of lung adenocarcinoma in smokers, making it a potential diagnostic and/or prognostic marker (1, 6, 7). AKR1B10 is an enzyme that efficiently catalyzes the reduction of carbonyls to corresponding alcohols with NADPH as a co-enzyme (1). Recent studies demonstrate that AKR1B10 expression facilitates growth of cancer cells, enhances their clonogenic capability, and reduces their susceptibility to reactive carbonyls such as acrolein and crotonaldehyde (8, 9). In vitro, AKR1B10 also shows strong enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal, reducing them to the corresponding retinols. The diversity of retinal metabolism may diminish intracellular retinoic acid, a signaling molecule regulating cell proliferation and differentiation (4, 10).The current study presents a novel biological function of AKR1B10, regulating long chain fatty acid synthesis, in human breast cancer cells. During tumorigenic transformatio...

Transition between epithelial and mesenchymal states is a feature of both normal development and tumor progression. We report that expression of chloride channel accessory protein hCLCA2 is a characteristic of epithelial differentiation in the immortalized MCF10A and HMLE models, while induction of EMT by cell dilution, TGFbeta, or mesenchymal transcription factors sharply reduces hCLCA2 levels. Attenuation of hCLCA2 expression by lentiviral shRNA caused cell overgrowth and focus formation, enhanced migration and invasion, and increased mammosphere formation in methylcellulose. These changes were accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers such as vimentin and fibronectin. Moreover, hCLCA2 expression is greatly downregulated in breast cancer cells with a mesenchymal or claudin-low profile. These observations suggest that loss of hCLCA2 may promote metastasis. We find that higher-than-median expression of hCLCA2 is associated with a one-third lower rate of metastasis over an 18 year period among breast cancer patients compared to lower-than-median (n=344, unfiltered for subtype). Thus, hCLCA2 is required for epithelial differentiation, and its loss during tumor progression contributes to metastasis. Overexpression of hCLCA2 has been reported to inhibit cell proliferation and is accompanied by increases in chloride current at the plasma membrane and reduced intracellular pH (pHi). We found that knockdown cells have sharply reduced chloride current and higher pHi, both characteristics of tumor cells. These results suggest a mechanism for the effects on differentiation. Loss of hCLCA2 may allow escape from pHi homeostatic mechanisms, permitting the higher intracellular and lower extracellular pH that are characteristic of aggressive tumor cells.

A novel breast cancer cell line (RAO-3) was established by transduction of the Q61L mutant RAS into human mammary epithelial cells that were immortalized with catalytic subunit of telomerase (hTERT). The cells displayed anchorage-independent growth and proliferation, and formed human mammary spindle cell carcinoma when injected into nude mice. Chromosome locus 1q22-23 was partially duplicated and inverted on one of the 3 chromosomes present in the cell line. We report here that mutations of chromosome 1q22-23 locus have resulted in the loss of RAB25 expression in the breast cancer cell line. Transduction of RAB25 into the breast cancer cell line arrests anchorage-independent growth. We have also demonstrated loss of RAB25 in human breast tumor tissue. These data suggest that loss of RAB25 might contribute to tumorigenesis of breast cancer, and RAB25 is likely to be an important factor in the development of breast cancer. RAB25 could be used as biological marker of breast cancer and provides a target for gene replacement therapy. ' 2006 Wiley-Liss, Inc. Key words: RAS; RAB25; breast cancerBreast cancer is the most common cancer in North American women. Many genes are considered to contribute to tumorigenesis of the mammary gland, such as RAS, BCL-2 (B-cell Leukemia-2) and NRG1 (Neuregulin1). 1-3 A novel series of human breast cancer cell lines has been established through the use of defined genetic elements in an effort to better define the role of various oncogenes in a stepwise model to tumor progression. 4 Human mammary epithelial cells (HMEC) from healthy individuals undergoing reduction mammoplasty were immortalized by transduction of either the catalytic subunit of telomerase (hTERT) after passage through stasis (RAO-1 cell line) or the human papilloma virus type16 (HPV16) E6/E7 genes. The RAO-1 cell line was then transduced with the Q61L mutant H-RAS gene; RAO-2 is a RAS-transduced derivative cell line of RAO-1 that does not show anchorageindependent growth in soft agar and is not tumorigenic in nude mice. RAO-3 and RAO-4 are human breast cancer cell lines that were derived from RAO-1 after RAS transduction. RAO-3 exclusively gives rise to human mammary spindle cell carcinomas when injected into nude mice. RAO-4 exclusively generates human mammary epithelial carcinoma when injected into nude mice. Previous studies suggested that a critical cytogenetic event on chromosome locus 1q23 was the last significant step to transformation in our RAS-driven model. 4 We confirmed the rearrangement of chromosome 1q22-23 by FISH (fluorescence in situ hybridization) in the RAO-3 cell line. The expression of RAB25, one of the genes that are located in this region, was lost in some of the tumorigenic cell lines that we tested, including RAO-3 and RAO-4.The RAB guanosine triphosphatases (GTPases) (RAS-related in brain) 5 belong to the RAS superfamily of small GTPases. More than 60 different RAB family members have been identified in the human genome. 6,7 The human RAS family consists of 3 protooncogenes, H-RAS, K-RAS and N...

No abstract