Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients

Slug, a member of the Snail family of transcription factors, plays a crucial role in the regulation of epithelial-mesenchymal transition (EMT) by suppressing several epithelial markers and adhesion molecules including E-cadherin. Recently, several studies have reported Slug to be expressed in breast carcinoma, oesophageal carcinoma accompanied with shorter survival. In this study, we first investigated expression of Slug mRNA in five colorectal carcinoma cell lines by reverse transcription–polymerase chain reaction. Furthermore, we investigated Slug and E-cadherin expression by immunohistochemistry in 138 patients with colorectal carcinoma. Slug mRNA was clearly expressed in four out of five colorectal carcinoma cell lines. Positive expression of Slug and E-cadherin was observed in 37 and 58% of cases, respectively. The positive expression of Slug was significantly associated with Dukes stage and distant metastasis (P=0.0027 and 0.0007), and the positive expression of Slug had a significant impact on patient overall survival (P<0.0001, log-rank test). Moreover, patients with positive expression of Slug and reduced expression of E-cadherin showed the worst prognosis (P<0.0001, log-rank test). Multivariate analysis indicated that Slug expression was an independent prognostic factor. These results suggest that positive Slug expression in colorectal carcinoma patients may become a significant parameter of poor prognosis

Zinc Overload Enhances APP Cleavage and Aβ Deposition in the Alzheimer Mouse Brain

BACKGROUND: Abnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro. CONCLUSIONS/SIGNIFICANCE: The present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD

Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models

Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric Aβ. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, Aβ plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the ‘generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited

Trends in Market Demand for Internal Medicine 1999 to 2004: An Analysis of Physician Job Advertisements

BACKGROUND: The health care marketplace has changed substantially since the last assessment of demand for internal medicine physicians in 1996. METHODS: We reviewed internal medicine employment advertisements published in 4 major medical journals between 1996 and 2004. The number of positions, specialty, and other practice characteristics (e.g., location) were collected from each advertisement. RESULTS: Four thousand two hundred twenty-four advertisements posted 4,992 positions. Of these positions, jobs in the Northeast (31% of positions) or single specialty groups (36.8% of positions) were most common. The relative proportion of advertisements for nephrologists declined (P<.001), while the relative proportions of advertisements for critical care specialists (0.5% in 1996 to 1.7% in 2004, P = .004) and hospitalists (1.0% in 1996 to 12.1% in 2004, P<.001) increased. Advertisements for outpatient-based generalist positions (i.e., Primary Care and Internal Medicine) declined (−2.7% relative annual change, 95% confidence interval [95% CI] −4.1%, −1.2%) between 1996 and 2004, a decrease largely due to a substantial decline in advertisements noted between 1996 and 1998. However, over the entire time period, the combined proportion of advertisements for all generalists (hospitalists and outpatient-based generalists) did not change (0.5% relative annual change, 95% CI −0.8% to 2.0%). CONCLUSIONS: Since 1996, demand for the majority of medical subspecialties has remained constant while relative demand has decreased for primary care and increased for hospitalists and critical care. Increase in demand for generalist-trained hospitalists appears to have offset falling demand for outpatient generalists