Browsing by Subject "Colon cancer"
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Item AUCTSP: an improved biomarker gene pair class predictor(BMC, 2018-06-26) Kagaris, Dimitri; Khamesipour, Alireza; Yiannoutsos, Constantin T.; Biostatistics, School of Public HealthThe Top Scoring Pair (TSP) classifier, based on the concept of relative ranking reversals in the expressions of pairs of genes, has been proposed as a simple, accurate, and easily interpretable decision rule for classification and class prediction of gene expression profiles. The idea that differences in gene expression ranking are associated with presence or absence of disease is compelling and has strong biological plausibility. Nevertheless, the TSP formulation ignores significant available information which can improve classification accuracy and is vulnerable to selecting genes which do not have differential expression in the two conditions ("pivot" genes). RESULTS: We introduce the AUCTSP classifier as an alternative rank-based estimator of the magnitude of the ranking reversals involved in the original TSP. The proposed estimator is based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) and as such, takes into account the separation of the entire distribution of gene expression levels in gene pairs under the conditions considered, as opposed to comparing gene rankings within individual subjects as in the original TSP formulation. Through extensive simulations and case studies involving classification in ovarian, leukemia, colon, breast and prostate cancers and diffuse large b-cell lymphoma, we show the superiority of the proposed approach in terms of improving classification accuracy, avoiding overfitting and being less prone to selecting non-informative (pivot) genes. CONCLUSIONS: The proposed AUCTSP is a simple yet reliable and robust rank-based classifier for gene expression classification. While the AUCTSP works by the same principle as TSP, its ability to determine the top scoring gene pair based on the relative rankings of two marker genes across all subjects as opposed to each individual subject results in significant performance gains in classification accuracy. In addition, the proposed method tends to avoid selection of non-informative (pivot) genes as members of the top-scoring pair.Item Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls(Wiley, 2019-09) Agalliu, llir; Ortega, Roberto A.; San Luciano, Marta; Mirelman, Anat; Pont-Sunyer, Claustre; Brockmann, Kathrin; Vilas, Dolores; Tolosa, Eduardo; Berg, Daniela; Warø, Bjørg; Glickman, Amanda; Raymond, Deborah; Inzelberg, Rivka; Ruiz-Martinez, Javier; Mondragon, Elisabet; Friedman, Eitan; Hassin-Baer, Sharon; Alcalay, Roy N.; Mejia-Santana, Helen; Aasly, Jan; Foroud, Tatiana; Marder, Karen; Giladi, Nir; Bressman, Susan; Saunders-Pullman, Rachel; Medical and Molecular Genetics, School of MedicineBACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.Item Delivery of adjuvant chemotherapy (AC) to veterans with resected colon cancer(ASCO Annual Meeting, 2012-06) Riggs, Heather D.; Lane, Kathleen A.; Loehrer, Patrick J.; Hui, Sui; Rawl, Susan M.; Ormerod, Anne; Weiner, MichaelPatients with incomplete administration of AC for colon cancer (CC) likely experience inferior survival while oxaliplatin- and capecitabine-containing AC may not improve survival for older patients. The influence on AC completion of age, other baseline patient characteristics, or regimen characteristics is unknown. We evaluated the association of baseline characteristics and planned AC regimen with AC delivery in resected CC patients.Item Identification of colorectal cancer using structured and free text clinical data(Sage, 2022) Redd, Douglas F.; Shao, Yijun; Zeng-Treitler, Qing; Myers, Laura J.; Barker, Barry C.; Nelson, Stuart J.; Imperiale, Thomas F.; Medicine, School of MedicineColorectal cancer incidence has continually fallen among those 50 years old and over. However, the incidence has increased in those under 50. Even with the recent screening guidelines recommending that screening begins at age 45, nearly half of all early-onset colorectal cancer will be missed. Methods are needed to identify high-risk individuals in this age group for targeted screening. Colorectal cancer studies, as with other clinical studies, have required labor intensive chart review for the identification of those affected and risk factors. Natural language processing and machine learning can be used to automate the process and enable the screening of large numbers of patients. This study developed and compared four machine learning and statistical models: logistic regression, support vector machine, random forest, and deep neural network, in their performance in classifying colorectal cancer patients. Excellent classification performance is achieved with AUCs over 97%.Item Impact of Quantitative Information and a Nudge on Attitudes toward Colorectal Cancer Screening(Society for Medical Decision Making, 2010-10-25) Schwartz, Peter H.; Imperiale, Thomas F.; Kloss, Holly N.; Perkins, Susan M.; Rawl, Susan M.; Sachs, Greg A.; Meslin, Eric M.Research in behavioral economics suggests that individuals facing complex decisions benefit from being given a “nudge” towards one option, especially in situations where making any choice, as opposed to none, is preferred. Decisions about colorectal cancer (CRC) screening are of this type, since several tests are recommended by guidelines, including colonoscopy, sigmoidoscopy, and stool testing. No studies have examined the use of a nudge in the context of CRC screening. In this study, we compared the effects of two different approaches to providing quantitative information about CRC risk and benefits of screening, one with and one without a nudge towards fecal immunochemical testing (FIT) (a stool test).Item Novel Serine 176 Phosphorylation of YBX1 Activates NF-κB in Colon Cancer(American Society for Biochemistry and Molecular Biology, 2017-02-24) Martin, Matthew; Hua, Laiqing; Wang, Benlian; Wei, Han; Prabhu, Lakshmi; Hartley, Antja-Voy; Jiang, Guanglong; Liu, Yunlong; Lu, Tao; Medical and Molecular Genetics, School of MedicineY box protein 1 (YBX1) is a well known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Previously, we have shown that YBX1 could function as a tumor promoter through phosphorylation of its Ser-165 residue, leading to the activation of the NF-κB signaling pathway (1). In this study, using mass spectrometry analysis, we discovered a distinct phosphorylation site, Ser-176, on YBX1. Overexpression of the YBX1-S176A (serine-to-alanine) mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB-activating ability compared with that of WT-YBX1, confirming that Ser-176 phosphorylation is critical for the activation of NF-κB by YBX1. Importantly, the mutant of Ser-176 and the previously reported Ser-165 sites regulate distinct groups of NF-κB target genes, suggesting the unique and irreplaceable function of each of these two phosphorylated serine residues. Our important findings could provide a novel cancer therapy strategy by blocking either Ser-176 or Ser-165 phosphorylation or both of YBX1 in colon cancer.Item Pre-Diagnostic Telomere Length and Colorectal Cancer Risk(Elsevier, 2022) Yang, Keming; Prescott, Jennifer; Hazra, Aditi; Meyerhardt, Jeffrey A.; Zhang, Xuehong; De Vivo, Immaculata; Chan, Andrew T.; Du, Mengmeng; Giovannucci, Edward L.; Nan, Hongmei; Community and Global Health, Richard M. Fairbanks School of Public HealthBackground: Progressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent. Methods: We examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336). Results: We did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest) = 1.36 (0.85, 2.17), P-trend = 0.27; OR (95% CI) per 1 SD decrease in TL = 1.12 (0.92, 1.36)]. Conclusions: Our prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.Item The presence of telomere fusion in sporadic colon cancer independently of disease stage, TP53/KRAS mutation status, mean telomere length, and telomerase activity(Elsevier, 2014-10) Tanaka, Hiromi; Beam, Matthew J.; Caruana, Kevin; Medical & Molecular Genetics, School of MedicineDefects in telomere maintenance can result in telomere fusions that likely play a causative role in carcinogenesis by promoting genomic instability. However, this proposition remains to be fully understood in human colon carcinogenesis. In the present study, the temporal sequence of telomere dysfunction dynamics was delineated by analyzing telomere fusion, telomere length, telomerase activity, hotspot mutations in KRAS or BRAF, and TP53 of tissue samples obtained from 18 colon cancer patients. Our results revealed that both the deficiency of p53 and the shortening of mean telomere length were not necessary for producing telomere fusions in colon tissue. In five cases, telomere fusion was observed even in tissue adjacent to cancerous lesions, suggesting that genomic instability is initiated in pathologically non-cancerous lesions. The extent of mean telomere attrition increased with lymph node invasiveness of tumors, implying that mean telomere shortening correlates with colon cancer progression. Telomerase activity was relatively higher in most cancer tissues containing mutation(s) in KRAS or BRAF and/or TP53 compared to those without these hotspot mutations, suggesting that telomerase could become fully active at the late stage of colon cancer development. Interestingly, the majority of telomere fusion junctions in colon cancer appeared to be a chromatid-type containing chromosome 7q or 12q. In sum, this meticulous correlative study not only highlights the concept that telomere fusion is present in the early stages of cancer regardless of TP53/KRAS mutation status, mean telomere length, and telomerase activity, but also provides additional insights targeting key telomere fusion junctions which may have significant implications for colon cancer diagnoses.Item Recruitment strategies and design considerations in a trial of resistance training to prevent dose-limiting toxicities in colon cancer patients undergoing chemotherapy(Elsevier, 2021) Caan, Bette J.; Meyerhardt, Jeffrey A.; Brown, Justin C.; Campbell, Kristin L.; Cespedes Feliciano, Elizabeth M.; Lee, Catherine; Ross, Michelle C.; Quinney, Sara; Quesenberry, Charles; Sternfeld, Barbara; Schmitz, Kathryn H.; Obstetrics and Gynecology, School of MedicineLow muscle is associated with an increased risk of chemotherapy-related dose limiting toxicities (DLT) in cancer patients. Resistance training (RT) improves muscle mass; however, the effects of RT on preventing DLTs and dose reductions in colon cancer patients has not been investigated. FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) is a multicenter, randomized clinical trial examining the effects of RT on relative dose intensity (RDI; primary outcome) and moderate and severe chemotoxicities (primary outcome) in non-metastatic colon cancer patients receiving adjuvant chemotherapy. Patients (N = 180) will be recruited from Kaiser Permanente Northern California, Dana-Farber Cancer Institute, and Penn State Cancer Institute. This paper describes recruitment strategies and design considerations. Patients will be randomized in equal numbers to RT intervention or control. Patients have baseline and post completion of chemotherapy visits where information on anthropometry, physical function, body composition, quality of life, physical activity and dietary behaviors, and inflammatory blood markers will be collected. Patient-reported outcomes of chemotherapy side effects will be collected around the time of chemotherapy throughout the duration of the trial. Intervention participants will be prescribed a progressive RT program consisting of 4-6 visits with a certified exercise trainer, delivered either in-person or remotely by video conference, and will be asked to engage twice weekly in-home training sessions. Control patients at the end of the study receive a consult with a FORCE exercise trainer, an online exercise RT training program and a set of resistance bands. Results of this trial will provide information on the benefit of resistance exercise as a treatment to increase RDI.Item Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment(Oxford Academic, 2016-07-01) Shields, Christina E. DeStefano; Van Meerbeke, Sara W.; Housseau, Franck; Wang, Hao; Huso, David L.; Casero, Robert A., Jr.; O’ Hagan, Heather M.; Sears, Cynthia L.; Medicine, School of MedicineBACKGROUND: Chronic inflammation and composition of the colon microbiota have been associated with colorectal cancer in humans. The human commensal enterotoxigenic Bacteroides fragilis (ETBF) is linked to both inflammatory bowel disease and colorectal cancer and, in our murine model, causes interleukin 17A (IL-17A)-dependent colon tumors. In these studies, we hypothesized that persistent colonization by ETBF is required for tumorigenesis. METHODS: We established a method for clearing ETBF in mice, using the antibiotic cefoxitin. Multiple intestinal neoplasia mice were colonized with ETBF for the experiment duration or were cleared of infection after 5 or 14 days. Gross tumors and/or microadenomas were then evaluated. In parallel, IL-17A expression was evaluated in wild-type littermates. RESULTS: Cefoxitin treatment resulted in complete and durable clearance of ETBF colonization. We observed a stepwise increase in median colon tumor numbers as the duration of ETBF colonization increased before cefoxitin treatment. ETBF eradication also significantly decreased mucosal IL-17A expression. CONCLUSIONS: The timing of ETBF clearance profoundly influences colon adenoma formation, defining a period during which the colon is susceptible to IL-17A-dependent tumorigenesis in this murine model. This model system can be used to study the microbiota-dependent and molecular mechanisms contributing to IL-17A-dependent colon tumor initiation.