Citations

Abstract Background: Inflammation is hypothesized to play a role in colorectal tumorigenesis. Circulating levels of C-reactive protein (CRP), a serologic marker of the inflammatory response, have been positively associated with colorectal cancer development in some studies; however, there are limited data on the relation of CRP with colorectal adenomas, established precursors of colorectal cancer. Methods: A nested case–control investigation of CRP levels and incident colorectal adenoma was conducted in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a randomized trial of 154,942 individuals designed to test the efficacy of flexible sigmoidoscopy on colorectal cancer mortality when performed once, and then repeated 3 to 5 years later. Serum CRP levels were measured in baseline blood specimens from participants who were free of polyps in the left-sided colorectum at the baseline screening procedure, but who were found at the subsequent screen to have at least one colorectal adenoma (n = 356), and in a set of polyp-free, frequency-matched controls (n = 396). Results: In a multivariable logistic regression model that included established colorectal adenoma risk factors, a 1-unit increase in log CRP level was associated with a 15% reduction in risk of developing colorectal adenoma (OR = 0.85, 95% CI, 0.75–0.98, Ptrend = 0.01). This association did not differ according to body size, smoking behavior, gender, use of nonsteroidal antiinflammatory drugs, or adenoma location. Conclusions: High circulating CRP levels may be protective against colorectal adenoma development. Impact: Though at contrast with mechanistic data on inflammation and colorectal tumorigenesis, this finding is not inconsistent with prior results on CRP and colorectal adenoma and warrants further investigation. Cancer Epidemiol Biomarkers Prev; 20(3); 537–44. ©2011 AACR.

Abstract Purpose: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) upon the prognosis of colon cancer survivors and its relationship to gender remains unknown. Experimental Design: BMI (kg/m2) was categorized in patients with TNM stage II and III colon carcinomas (n= 4,381) enrolled in 7 randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Cox proportional hazards models were used to determine the association of BMI with disease-free (DFS) and overall survival (OS). Results: Among colon cancer patients, 868 (20%) were obese (BMI >30 kg/m2) of which 606 were class 1 (BMI 30-34 kg/m2) and 262 were class 2,3 (BMI >35 kg/m2). Obese versus normal-weight patients were more likely to be younger (p=0.038), have distal tumors (0.058), show intact DNA mismatch repair (MMR) (p=0.035), and have more lymph node metastases (p=0.017). In a multivariate analysis, BMI was significantly associated with both DFS (p=0.030) and OS (p=0.0017). Men with class 2,3 obesity showed reduced OS compared to normal weight men [HR 1.35 (1.02, 1.79); p=0.039]. Women with class I obesity had reduced OS [HR 1.24 (1.01, 1.53), p=0.045] compared to normal weight women. Overweight status was associated with improved OS in men (p= 0.006) and underweight women had significantly worse OS (p= 0.019). BMI was not predictive of therapeutic benefit. Conclusions: Obesity is an independent prognostic variable in colon cancer survivors and shows gender-related differences. These data suggest that obesity-related biological factors can influence clinical outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 904.

Abstract BACKGROUND. Autophagy is a mechanism of cellular destruction whereby cytoplasmic proteins and organelles are sequestered in vacuoles and delivered to lysosomes for degradation and recycling. Autophagy is not always pro-death but can also be pro-survival under conditions of cellular stress. Autophagy and apoptosis can be regulated by Bcl-2 family proteins. We determined whether the anti-neoplastic agent celecoxib can induce autophagy and/or apoptosis, and if a small molecule Bcl-2/Bcl-xL antagonist, e.g., ABT-737, can enhance either/both processes. Furthermore, we determined whether autophagy inhibition can drive colon cancer cells into apoptosis. EXPERIMENTAL METHODS. Human colon cancer cell lines (HCT116, SW480 ± Bcl-2, HT-29 ± Bcl-xL lentiviral shRNA) were incubated with celecoxib (0-120 µM) alone and in combination with ABT-737 (0- 5 µM). Autophagy was studied by LC3I/II expression (Western blotting) and using a GFP-LC3B chimeric plasmid. Additionally, autophagy was imaged by monodansylcadaverine (MDC) staining of autophagic vacuoles and acridine orange staining of acidic vesicles by fluorescent confocal microscopy. Apoptosis was analyzed by caspase cleavage (Western blotting) by annexin V labeling and FACS. RESULTS. Celecoxib triggered conversion of the autophagosome-associated protein light chain 3 (LC3) from a cytosolic (LC3I) to a membrane-bound (LC3II) form as shown by Western blotting, and a change in the localization of the fluorescence pattern of an ectopic GFP-LC3B protein. Celecoxib-induced conversion of LC3 was due to autophagy induction, as shown using the lysosome inhibitor, Bafilomycin A1 that produced an accumulation of LC3II. Celecoxib-induced autophagy and apoptosis were attenuated by ectopic Bcl-2, but were augmented by Bcl-xL knockdown. ABT-737 was shown to enhance celecoxib-induced autophagy as shown by LC3 conversion, acridine orange staining of acidic vesicles, and MDC staining of autophagic vacuoles. Celecoxib also induced apoptosis, as shown by caspase cleavage and annexin V labeling, that was synergistically enhanced by ABT-737. Given that autophagy can be pro-survival under conditions of cellular stress, we determined whether inhibition of autophagy can drive cells into apoptosis. Use of the autophagy inhibitor 3-methyladenine (3-MA) was shown to block LC3 conversion and to enhance celecoxib-induced apoptosis that was further augmented by ABT-737. Similarly, Vps34 or Atg8/LC3 siRNA were shown to enhance caspase cleavage in cells treated with celecoxib plus ABT-737. CONCLUSION. Celecoxib induces autophagy and apoptosis that can both be potentiated by a Bcl-2/ Bcl-xL antagonist. Furthermore, inhibition of autophagy was shown to drive cells into apoptosis, suggesting a novel therapeutic strategy against colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4858.

The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance‐based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H2O2 and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH4)-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH4 therapy were studied. Both triple therapy and oral BH4 therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH4 levels and BH4-to-BH2 ratio similar to ANG rats with BH4 supplementation. Furthermore, triple therapy (but not oral BH4 therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH4 in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH4 levels and NOS3 phosphorylation at Ser1177.