Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormonerefractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signalregulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017-24]

Purpose: Prostate cancer metastasis to secondary organs is considered an initial event in the development of hormone refractory disease and remains the major cause of death among prostate cancer patients. In this study, we investigated the role of fascin, a cytoskeleton actinb undling protein involved in the formation of filopodia and cell migration, in prostate cancer progression. Experimental Design: Fascin protein expression was examined by immunohistochemistry in a cohort of 196 patients with localized prostate cancer and across several stages of disease progression, including hormone refractory disease. Cellular changes were also assessed in vitro and in vivo in DU145 prostate cancer cell line using fascin gene silencing. Results: Fascin epithelial expression was significantly up-regulated in localized and hormone refractory prostate cancer compared with benign prostate tissue (P < 0.05). Furthermore, high fascin expression was associated with an increased rate of prostate-specific antigen recurrence following radical prostatectomy (P = 0.075), signifying more aggressive clinical course, thus supporting a function for fascin in prostate cancer progression. In cellular models, fascin gene silencing using small interfering RNA in the androgen-independent prostate cancer cell line DU145 decreased cell motility and invasiveness while increasing cell adhesive properties. In addition, fascin small interfering RNA^expressing DU145 cells implanted orthotopically in mouse prostate showed significantly decreased growth (P < 0.005) and drastically prevented the formation of lymph node metastases (P < 0.001) compared with their matched controls. Conclusions:Our data show a function of fascin in the regulation of prostate cancer progression and emphasize the importance of fascin as a prognostic marker for aggressive disease and as a potential therapeutic target for advanced androgen independent disease.Prostate cancer remains one of the most prevalent cancers and a major source for morbidity and mortality in the Western world (1 -4). In 2007, f219,000 new patients were diagnosed with prostate cancer causing about 27,000 cancer related deaths (5). Disease progression and the development of hormone refractory disease remain major causes of cancer related death.To significantly alter the disease course, improved ways to understand, diagnose, and treat aggressive forms of metastatic prostate cancer are needed.Tumor cell motility is the hallmark of invasion and an essential step in metastasis (6, 7). Understanding the molecular pathways involved in tumor cell motility and how the tumor microenvironment contributes to cell migration and metastasis is critical to developing improved therapeutic targets for the treatment of metastatic prostate cancer. Predicting disease progression is a major and significant step in identifying patients at increased risk for cancer specific death. Therefore, one goal in the diagnosis and treatment of men with prostate cancer is to develop tissue-based molecular tests to distinguish ind...

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To investigate the role of the Montreal Cognitive Assessment (MoCA) (Beijing version) and its memory tasks on detecting different mild cognitive impairment (MCI) subtypes including amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in memory clinics. A total of 121 patients with MCI and 53 healthy controls were included. Fifty-six aMCI-multiple domains (amMCI), 32 aMCI-single domain (asMCI), and 33 naMCI patients were diagnosed according to extensive cognitive tests. All participants were administered by the Mini Mental State Examination (MMSE) and the MoCA. Patients with amMCI performed worse than patients with asMCI, naMCI, and healthy controls on the MMSE and the MoCA (p < 0.001). The area under the curve (AUC) value for the MoCA when comparing the amMCI and control groups was 0.884 (p < 0.001), which was superior to that of the MMSE. The AUC value decreased to 0.687 when applied to the naMCI and control groups (p = 0.007), which was still higher than that of the Rey Auditory Verbal Learning Test (RAVLT) or the Rey-Osterrieth complex figure (ROCF). Delayed free recall or category prompted recall in the MoCA had roles in differentiating asMCI and controls groups with AUC value of 0.717 (p = 0.002) and 0.691 (p = 0.005), respectively. The MoCA is a good screening tool for detecting different types of MCI and is suitable for patients in outpatient clinics.

Aims:In order to confirm the utility of the voxelbased specific regional analysis system for Alzheimer's disease (VSRAD) in assessing the atrophy of the entorhinal cortex, we investigated whether there were correlations between VSRAD and the scores of neuropsychological tests in the patients with Alzheimer's disease (AD) and mild cognitive impairment.Methods: Thirty patients, including 18 AD and 12 mild cognitive impairment patients, were included in this study. VSRAD was performed to assess the atrophy of the entorhinal cortex. The patients were carefully screened with the neuropsychological tests, including Wechsler Adult Intelligence Scale-III (WAIS-III), the Wechsler Memory Scale-Revised, the Alzheimer's Disease Assessment Scale-Cognitive Part (ADAS-cog) and the revised version of Hasegawa's Dementia Scale.Results: All patients showed atrophy with different degrees in the entorhinal cortex except one case. Z-scores had significant positive correlation with ADAS-cog, and negative correlation with Information subset of WAIS-III (respectively, P = 0.0129 and P = 0.0294). The revised version of Hasegawa's Dementia Scale and the Similarities subsets of the WAIS-III had a tendency of negatively correlating with Z-scores of VSRAD (respectively, P = 0.0532 and P = 0.0635). The Delayed Visual Reproduction subset of the Wechsler Memory Scale-Revised was also found to have a weak negative correlation with Z-scores (P = 0.0609).Conclusions: Z-scores of VSRAD were revealed to have a close relation with many neuropsychological tests, especially ADAS-cog and the Information subset of WAIS-III. The results meant that VSRAD was a useful indictor of early diagnosis of AD, closely correlating with the changes of cognitive functions and the progression of the disease.

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The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics.