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Item A complex signature network that controls the upregulation of PRMT5 in colorectal cancer(Elsevier, 2022-03) Wei, Han; Hartley, Antja-Voy; Motolani, Aishat; Jiang, Guanglong; Safa, Ahmad; Prabhu, Lakshmi; Liu, Yunlong; Lu, Tao; Pharmacology and Toxicology, School of MedicineItem Aberrant cholesterol metabolism in colorectal cancer represents a targetable vulnerability(Elsevier, 2023-07) Xie, Jingwu; Nguyen, Chi Mai; Turk, Anita; Nan, Hongmei; Imperiale, Thomas F.; House, Michael; Huang, Kun; Su, Jing; Biostatistics, School of Public HealthItem Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers(Impact Journals, 2017-05-23) Prabhu, Lakshmi; Wei, Han; Chen, Lan; Demir, Özlem; Sandusky, George; Sun, Emily; Wang, John; Mo, Jessica; Zeng, Lifan; Fishel, Melissa; Safa, Ahmad; Amaro, Rommie; Korc, Murray; Zhang, Zhong-Yin; Lu, Tao; Pharmacology and Toxicology, School of MedicinePancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.Item Adding Natural Frequency Data to a Decision Aid for Colorectal Cancer Screening: Results of a Randomized Trial(2013-10-22) Schwartz, Peter H.; Muriello, Paul F.; Perkins, Susan M.; Schmidt, Karen K.; Rawl, Susan M.Guidelines recommend that decision aids provide natural frequency data regarding baseline risk, risk reduction, and chances of false positives and negatives. Such quantitative information may confuse patients, especially those with low numeracy. We conducted a randomized trial to compare effects of 2 colorectal cancer (CRC) screening decision aids—one with and one without natural frequency data.Item Advances in CRC prevention: screening and surveillance(Elsevier, 2018) Dekker, Evelien; Rex, Douglas K.; Medicine, School of MedicineColorectal cancer (CRC) is amongst the most commonly diagnosed cancers and causes of death from cancer across the world. CRC can, however, be detected in asymptomatic patients at a curable stage, and several studies have shown lower mortality among patients who undergo screening compared to those who do not. Using colonoscopy in CRC screening also results in the detection of precancerous polyps that can be directly removed during the procedure, thereby reducing the incidence of cancer. In the past decade, convincing evidence has appeared that the effectiveness of colonoscopy as CRC prevention tool is associated with the quality of the procedure. This review aims to provide an up-to-date overview of recent efforts to improve colonoscopy effectiveness of by enhancing detection and improving the completeness and safety of resection of colorectal lesions.Item AGA White Paper: Roadmap for the Future of Colorectal Cancer Screening in the United States(Elsevier, 2020) Melson, Joshua E.; Imperiale, Thomas F.; Itzkowitz, Steven H.; Llor, Xavier; Kochman, Michael L.; Grady, William M.; Schoen, Robert E.; Burke, Carol; Shaukat, Aasma; Rabeneck, Linda; Ladabaum, Uri; Bresalier, Robert; Spiegel, Brennan; Yee, Judy; Wang, Thomas; Lieberman, David; Komanduri, Srinadh; Muthusamy, V. Raman; Dey, Neelendu; Medicine, School of MedicineItem Association between pre-diagnostic leukocyte mitochondrial DNA copy number and survival among colorectal cancer patients(Elsevier, 2020-10) Yang, Keming; Forman, Michele R.; Graham, Brett H.; Monahan, Patrick O.; Giovannucci, Edward L.; De Vivo, Immaculata; Chan, Andrew T.; Nan, Hongmei; Epidemiology, School of Public HealthBackground Mitochondrial DNA copy number (mtDNAcn) is considered a biomarker for mitochondrial function and oxidative stress. Although previous studies have suggested a potential relationship between mtDNAcn at the time of colorectal cancer (CRC) diagnosis and CRC prognosis, findings have been inconsistent, and no study has specifically investigated the association of pre-diagnostic mtDNAcn with CRC survival. Methods We examined the association of pre-diagnostic leukocyte mtDNAcn (measured by qPCR) with overall and CRC-specific survival among 587 patients in Nurses’ Health Study and Health Professionals Follow-Up Study. Cox models were constructed to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Results During a mean follow-up of 10.5 years, 395 deaths were identified; 180 were due to CRC. Overall, we did not observe significant associations between mtDNAcn and either overall or CRC-specific survival among all cases or by cancer location, grade, or stage. In an exploratory stratified analysis, a suggestive inverse association of mtDNAcn and overall death risk appeared among current smokers [HR (95 % CI) for 1 SD decrease in mtDNAcn = 1.50 (0.98, 2.32), P-trend = 0.06]. Reduced mtDNAcn and lower CRC-specific death risk was observed among patients aged ≤ 70.5 at diagnosis [HR (95 % CI) for 1 SD decrease of mtDNAcn = 0.71 (0.52, 0.97), P-trend = 0.03], ≤ 5 years from blood collection to diagnosis [HR (95 % CI) for 1 SD decrease in mtDNAcn = 0.65 (0.44, 0.96), P-trend = 0.03] and those consuming a low-inflammatory diet [HR (95 % CI) for 1 SD decrease in mtDNAcn = 0.61 (0.42, 0.88), P-trend = 0.009]. Conclusion no significant associations between pre-diagnostic leukocyte mtDNAcn and either overall or CRC-specific survival appeared but exploratory analysis identified potential sub-group associations.Item Association of small versus diminutive adenomas and the risk for metachronous advanced adenomas: data from the New Hampshire Colonoscopy Registry(Elsevier, 2019) Anderson, Joseph C.; Rex, Douglas K.; Robinson, Christina; Butterly, Lynn F.; Medicine, School of MedicineBackground and Aims Limited data are available to investigate the impact of index adenoma size on the risk of metachronous advanced adenomas. Our goal was to examine the impact of having small (5-9 mm) versus diminutive (<5 mm) adenomas on the future risk of advanced adenomas within the categories for polyps <1 cm currently used in the United States: 1 to 2 and 3 or more tubular adenomas. Methods We included data from individuals participating in the statewide, population-based New Hampshire Colonoscopy Registry (NHCR). Groups were based on index findings: (1) 1 to 2 adenomas <5 mm (both diminutive), (2) 1 to 2 adenomas <1 cm (one or both small), (3) 3 to 10 adenomas <5 mm (all diminutive), (4) 3 to 10 adenomas <1 cm (one or more small), and (5) advanced adenomas (AA). AAs were defined as adenomas ≥1cm or those with villous elements or high-grade dysplasia or colorectal cancer (CRC). Outcomes were the absolute and adjusted risk of metachronous AAs. Covariates included age, sex, body mass index, family history of CRC, lifestyle factors, presence of serrated polyps, and time since the index examination. Results After adjusting for the covariates, we observed that having 1 to 2 adenomas with at least one 5 to 9 mm adenoma (adjusted odds ratio [AOR], 1.54; 95% confidence interval [CI], 1.12-2.11), 3 to 10 diminutive adenomas (AOR, 1.75; 95% CI, 1.03-2.95), 3 to 10 adenomas <1 cm (1 or more small) (AOR, 2.14; 95% CI, 1.39-3.29) or AAs (AOR, 2.77; 95% CI, 2.05-3.74) were associated with an increased risk for metachronous AA compared with having 1 to 2 diminutive adenomas. A further stratification of group 2 showed that those with exactly 2 small adenomas had an absolute risk of future AA of 7.6% (11/144) (95% CI, 4.3%-13.2%), higher than the absolute risk in the 1 to 2 diminutive polyp group, and similar to the risk for 3 to 10 adenomas of 8.2% (95% CI, 5.4-11.9). Conclusions For individuals with 1 to 2 adenomas <1 cm, having at least 1 small adenoma increased the metachronous risk of AA compared with having only diminutive adenomas. Furthermore, the subset with 2 small adenomas had a risk of future AA similar to the risk for 3 to 10 adenomas. These data suggest that individuals with at least 1 small adenoma may be at higher risk for future AAs and thus require closer follow-up than those with only diminutive adenomas. These data may be valuable to guideline committees for the creation of future surveillance recommendations.Item Associations between lifestyle factors and quality of life among older long-term breast, prostate, and colorectal cancer survivors(Wiley, 2009) Mosher, Catherine E.; Sloane, Richard; Morey, Miriam C.; Snyder, Denise Clutter; Cohen, Harvey J.; Miller, Paige E.; Demark-Wahnefried, WendyBACKGROUND: Older cancer survivors are at increased risk for secondary cancers, cardiovascular disease, obesity, and functional decline and, thus, may benefit from health-related interventions. However, to the authors' knowledge, little is known regarding the health behaviors of older cancer survivors and the associations of those behaviors with quality-of-life outcomes, especially during the long-term post-treatment period. METHODS: In total, 753 older (aged ≥65 years) long-term survivors (≥5 years postdiagnosis) of breast, prostate, and colorectal cancer completed 2 baseline telephone interviews to assess their eligibility for a diet and exercise intervention trial. The interviews assessed exercise, diet, weight status, and quality of life. RESULTS: Older cancer survivors reported a median of 10 minutes of moderate-to-vigorous exercise per week, and only 7% had Healthy Eating Index scores >80 (indicative of healthful eating habits relative to national guidelines). Despite their suboptimal health behaviors, survivors reported mental and physical quality of life that exceeded age-related norms. Greater exercise and better diet quality were associated with better physical quality-of-life outcomes (eg, better vitality and physical functioning; P < .05), whereas greater body mass index was associated with reduced physical quality of life (P < .001). CONCLUSIONS: The current results indicated a high prevalence of suboptimal health behaviors among older, long-term survivors of breast, prostate, and colorectal cancer who were interested in lifestyle modification. In addition, the findings pointed to the potential negative impact of obesity and the positive impact of physical activity and a healthy diet on physical quality of life in this population. Cancer 2009.Item Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells(AACR, 2019-05) Yang, Wanshui; Liu, Li; Keum, NaNa; Qian, Zhi Rong; Nowak, Jonathan A.; Hamada, Tsuyoshi; Song, Mingyang; Cao, Yin; Nosho, Katsuhiko; Smith-Warner, Stephanie A.; Zhang, Sui; Masugi, Yohei; Ng, Kimmie; Kosumi, Keisuke; Ma, Yanan; Garrett, Wendy S.; Wang, Molin; Nan, Hongmei; Giannakis, Marios; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Nishihara, Reiko; Wu, Kana; Giovannucci, Edward L.; Ogino, Shuji; Zhang, Xuehong; Epidemiology, School of Public HealthCalcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.