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Paul J Limburg

Publications and source records attributed to Paul J Limburg.

At least 19 recordsLinked to original sources
PubMed2007

A high-throughput 3-parameter flow cytometry-based cell death assay.

Apoptosis plays a role in many disease states, and the evaluation of novel therapeutics that alters the apoptotic cascade is an area of intense investigation. However, many generally available methods to evaluate cell death are either time consuming, imprecise, or both. We report a system that permits simultaneous evaluation of three apoptotic markers (cell membrane integrity, mitochondrial membrane potential, and cell cycle progression) with minimal technical manipulation. This system is particularly well-suited for toxicologic evaluation of novel compounds and profiling of new apoptosis-inducing agents.

Apoptosis↗
PubMed2006

Gene expression differences in normal esophageal mucosa associated with regression and progression of mild and moderate squamous dysplasia in a high-risk Chinese population.

A randomized, double-blinded, placebo-controlled 2 x 2 factorial chemoprevention trial was conducted in Linxian, China to assess the effects of selenomethionine and celecoxib on the natural history of esophageal squamous dysplasia. Results from this study indicated that asymptomatic adults with mild dysplasia were more likely to show an improvement when treated with selenomethionine compared with placebo (P = 0.02). Prompted by this finding, we examined the molecular profiles associated with regression and progression of dysplastic lesions in normal mucosa from 29 individuals, a subset of the Linxian cohort, using the Affymetrix U133A chip. Twenty differentially expressed genes were associated with regression and 129 were associated with progression when we compared the change in gene expression over time. Genes associated with immune response (n = 15), cell cycle (n = 15), metabolism (n = 15), calcium transport or calcium ion activity (n = 10), regulation of transcription (n = 9), signal transduction (n = 7), cytoskeleton and microtubules (n = 5), nucleotide processing and biosynthesis (n = 4), G-coupled signaling (n = 4), and apoptosis (n = 3) were present in the list of 149 genes. Using the Expression Analysis Systematic Explorer pathway analysis program, only the immune response pathway was significantly overrepresented among these 149 genes. Individuals whose lesions regressed seemed to have higher expression of genes associated with immune stimulation, such as antigen presentation, survival of T cells, and T-cell activation (HLA-DRA, HLA-DPA1, HLA-DBQ1, CD58, and FCER1A). In contrast, individuals whose lesions progressed had higher expression of genes involved in immune suppression and inflammation (CNR2, NFATC4, NFRKB, MBP, INHBB, CMKLR1, CRP, ORMS, SERPINA7, and SERPINA1). These data suggest that local and systemic immune responses may influence the natural history of esophageal squamous dysplasia.

Carcinoma, Squamous Cell↗
PubMed2006

Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study.

OBJECTIVES: Patients with type 2 diabetes mellitus (DM) may be at increased colorectal cancer (CRC) risk. However, existing data are inconsistent. We investigated CRC risks, overall and by anatomic subsite, within a population-based inception cohort of clinically confirmed type 2 DM subjects. METHODS: All residents of Rochester, Minnesota who first met standardized criteria for type 2 DM from 1970 to 1994 (997 men and 978 women) were identified and followed forward in time until emigration, death, or December 31, 1999. Incident CRC cases were identified by review of inpatient and outpatient medical records. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated to compare CRC incidence within the type 2 DM inception cohort with previously published rates for the Rochester general population. RESULTS: Over 19,158 person-years of follow-up, 51 incident CRC cases were identified within the type 2 DM cohort, while only 36.8 cases were expected (SIR = 1.39, 95% CI 1.03-1.82). Among men, type 2 DM was associated with increased overall (SIR = 1.67, 95% CI 1.16-2.33) and proximal (SIR = 1.96, 95% CI 1.16-3.10) CRC risks; distal CRC risk was also increased, but the point estimate was not statistically significant (SIR = 1.43, 95% CI 0.82-2.32). Among women, type 2 DM was not a risk factor for overall, proximal, or distal CRC (SIR = 1.03, 95% CI 0.60-1.66; SIR = 1.17, 95% CI 0.58-2.09; and SIR = 0.74, 95% CI 0.24-1.72, respectively). Within the type 2 DM cohort, current and former cigarette smokers were at higher CRC risk (SIR = 1.77, 95% CI 1.24-2.47) than never smokers (SIR = 0.99, 95% CI 0.57-1.61) and the interaction between type 2 DM and cigarette smoking status was statistically significant (p= 0.05). CONCLUSIONS: In this population-based, retrospective cohort study, clinically confirmed type 2 DM was associated with increased CRC risk, predominantly among men. Cigarette smoking appeared to positively modify DM-associated CRC risk, which to our knowledge has not been previously reported. These data suggest that further investigation of potential interactions between endogenous and exogenous factors involved in colorectal carcinogenesis may help to clarify the magnitude and extent of CRC risk experienced by persons with type 2 DM.

Chi-Square Distribution↗
PubMed2006

Visceral fat analysis at CT colonography.

RATIONALE AND OBJECTIVES: Obesity is associated with increased risks for colorectal neoplasia. Few studies have examined quantitative body fat measurements as predictors of colorectal polyps. The objective is to determine whether visceral fat is associated with colorectal polyps at computed tomography (CT) colonography. MATERIALS AND METHODS: Case (n = 25) and control (n = 25) subjects with proven large (>1 cm) colorectal adenomas or normal colons respectively were randomly selected from among an established CT colonography research study cohort. Using supine CT colonography data, the body wall was traced at three levels: top of the right kidney, iliac crest, and superior acetabulum. Total area from the three slices and each slice area were determined within the visceral fat range (-170 to -45 Hounsfield units) and recorded within the selected region. Visceral fat measures were compared between patient groups with and without polyps. RESULTS: None of the single slice visceral fat area measures or summed measures predicted case or control status. The most informative visceral fat measure was obtained at the top of the right kidney with a maximum area under the received operator characteristic curve of 0.77 (0.05 SE). For a selected sensitivity of 75%, the maximum specificity for a large (>or=1 cm) polyp was 64%. CONCLUSION: In this pilot study, visceral fat measures at CT colonography were not significantly associated with the presence of large colorectal adenomas. However, odd ratios were elevated by a factor of 2. This suggests that a larger study may be justified.

Aged↗
PubMed2006

Colorectal cancer prognosis among patients with inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is associated with an increased risk for colorectal cancer (CRC). However, the genetic, endoscopic, and histologic features of IBD-associated CRC differ from cancers that arise sporadically. The objectives of this study were to describe the clinicopathologic features of IBD-associated CRC and to compare survival rates between patients with IBD-associated CRC and patients with sporadic CRC. METHODS: There were 290 patients with IBD-associated CRC (241 with chronic ulcerative colitis [CUC] and 49 with Crohn's disease) and an equal number of age- and sex-matched sporadic CRC patients who were evaluated at the Mayo Clinic between 1976 and 1996. Medical records were reviewed retrospectively for demographic features, endoscopic and histologic characteristics, and vital status at the time of the last follow-up evaluation. The actuarial survival of each group was calculated by the Kaplan-Meier method. The influence of clinical features on survival was assessed using Cox proportional hazards regression modeling. RESULTS: The median age at diagnosis of IBD-related CRC was 48 years. Fifty-five percent of IBD-related tumors were distal to the splenic flexure compared with 78% of sporadic tumors. During a median follow-up period of 5 years, 163 IBD-associated CRC patients died (56%), compared with 164 sporadic CRC patients (57%). The 5-year survival rates were 54% in the IBD-CRC subgroup vs 53% in the sporadic CRC subgroup (P = .94, log-rank). CONCLUSIONS: CUC-related CRC is diagnosed at a relatively young age, and IBD-related tumors tend to be distributed more evenly across the colorectum than sporadic tumors. The survival rates for IBD-associated and sporadic CRC were similar.

Adolescent↗
PubMed2006

Insulin, glucose, insulin resistance, and incident colorectal cancer in male smokers.

BACKGROUND & AIMS: Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment-insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk, and none have reported associations on the basis of HOMA-IR. METHODS: We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n=29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin x fasting glucose/22.5. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models. RESULTS: Median (interquartile range) values for serum insulin, glucose, and HOMA-IR were 4.1 (2.9-7.2) mIU/L, 101 (94-108) mg/dL, and 0.99 (0.69-1.98) for case subjects and 4.1 (2.7-6.1) mIU/L, 99 (93-107) mg/dL, and 1.02 (0.69-1.53) for non-case subjects, respectively. On the basis of comparison of the highest versus lowest quartiles for each biomarker, insulin (HR, 1.84; 95% CI, 1.03-3.30) and HOMA-IR (HR, 1.85; 95% CI, 1.06-3.24) were significantly associated with incident CRC, whereas glucose was marginally associated with incident CRC (HR, 1.70; 95% CI, 0.92-3.13) in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (P trend=.12, .04, and .12, respectively), and multivariable adjustment generally attenuated the observed risk estimates. CONCLUSIONS: Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia, and/or insulin resistance as CRC risk factors.

Aged↗
PubMed2006

Nonsteroidal anti-inflammatory drugs and subsite-specific colorectal cancer incidence in the Iowa women's health study.

BACKGROUND: Previous epidemiologic studies have shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased colorectal cancer risk. However, few studies have examined associations between NSAID use and subsite-specific colorectal cancer risks. Because tumors of the proximal and distal colon differ with respect to their genetic alterations, clinicopathologic features, and demographic distribution, further investigation of subsite-specific colorectal cancer risks may be rewarding. METHODS: Data about aspirin and non-aspirin-NSAID use were recorded by self-report in 1992 among the initially cancer-free cohort of postmenopausal women in the Iowa Women's Health Study (n = 27,160). In total, 637 women developed colorectal cancer during the 11 years of follow-up, including 365 proximal colon, 132 distal colon, and 120 rectal cancer cases (11 overlapping and 9 not specified). RESULTS: For colon cancer, the multivariable-adjusted hazard ratios (HR) for women reporting use of aspirin two to five times and six or more times weekly (compared with nonusers of aspirin) were 0.79 [95% confidence interval (95% CI), 0.59-1.04] and 0.76 (95% CI, 0.58-1.00), respectively. The corresponding HRs for non-aspirin NSAIDs were 0.63 (95% CI, 0.41-0.96) and 0.85 (95% CI, 0.63-1.15), respectively. For proximal colon cancer, the multivariable-adjusted HRs for women reporting use of aspirin or non-aspirin NSAIDs two or more times weekly (compared with nonusers of each) were 0.67 (95% CI, 0.51-0.87) and 0.71 (95% CI, 0.52-0.97), respectively. No statistically significant association was found between either distal colon or rectal cancer and aspirin or non-aspirin NSAID use. DISCUSSION: Our study is consistent with a limited number of prior reports that have observed stronger associations between NSAID use and proximal versus distal colorectal cancer.

Aged↗
PubMed2006

Incidence of colorectal cancer in relation to glycemic index and load in a cohort of women.

BACKGROUND: Dietary glycemic index (GI) and glycemic load (GL) affect circulating insulin concentrations. Elevated circulating insulin concentrations can increase insulin-like growth factor-1, and both of these hormones may have growth-promoting effects within the colorectum. METHODS: We examined associations of GI and GL with colorectal cancer (CRC) among participants in the Iowa Women's Health Study (n = 35,197; ages 55-69 years at baseline in 1986). Over 15 years of follow-up, we identified 757 cases of colon cancer and 209 cases of rectal cancer (954 CRC cases). RESULTS: Overall, neither GI nor GL were significantly associated with incident CRC. However, among obese women (baseline body mass index >/=30 kg/m(2)) CRC incidence was increased in the highest versus lowest quintiles of GI (relative risk, 1.66; 95% confidence intervals, 1.13-2.43; P for trend = 0.02) and GL (relative risk, 1.79; 95% confidence intervals, 1.19-2.70; P for trend < 0.01). This pattern of increased risk for obese women with high GI or GL tended to hold for both colon cancer and rectal cancer, and for nondiabetic women as well. No statistically significant associations were observed between GI or GL and CRC among subjects whose baseline body mass index was <30 kg/m(2). CONCLUSION: Our findings suggest that high GI or GL are not major CRC risk factors among older women in general, but may increase CRC risk among women who are obese.

Aged↗
PubMed2006

Selenomethionine treatment does not alter gene expression in normal squamous esophageal mucosa in a high-risk Chinese population.

Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo. Using P < 0.001 as a cutoff, 11 differentially expressed genes were found in the SeMet supplementation group but these genes did not include either known selenoprotein genes or genes previously shown to be modulated by selenium treatment. Because the number of differentially expressed genes (n = 11) was less than expected by chance (n = 18), we concluded that SeMet supplementation had no measurable effect on gene expression in the normal squamous esophagus of these subjects with dysplasia.

Adult↗
PubMed2005

Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib.

BACKGROUND & AIMS: Esophageal squamous cell carcinoma remains a leading cause of cancer death worldwide. Squamous dysplasia, the accepted histological precursor for esophageal squamous cell carcinoma, represents a potentially modifiable intermediate end point for chemoprevention trials in high-risk populations. METHODS: We conducted a randomized, controlled trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2 factorial design) among residents of Linxian, People's Republic of China. Subjects had histologically confirmed mild or moderate esophageal squamous dysplasia at baseline. Esophagogastroduodenoscopy was performed before and after a 10-month intervention. Per-subject change (regression, stable, or progression) in the worst dysplasia grade was defined as the primary end point. Results were compared by agent group (selenomethionine vs placebo; celecoxib vs placebo). RESULTS: Two hundred sixty-seven subjects fulfilled all eligibility criteria, and 238 (89%) completed the trial. Overall, selenomethionine resulted in a trend toward increased dysplasia regression (43% vs 32%) and decreased dysplasia progression (14% vs 19%) compared with no selenomethionine (P = .08). In unplanned stratified analyses, selenomethionine favorably affected a change in dysplasia grade among 115 subjects with mild esophageal squamous dysplasia at baseline (P = .02), but not among 123 subjects with moderate esophageal squamous dysplasia at baseline (P = 1.00). Celecoxib status did not influence changes in dysplasia grade overall (P = .78) or by baseline histology subgroup. CONCLUSIONS: After a 10-month intervention, neither selenomethionine nor celecoxib inhibited esophageal squamous carcinogenesis for all high-risk subjects. However, among subjects with mild esophageal squamous dysplasia at baseline, selenomethionine did have a protective effect. Although it is based on unplanned stratified analyses, this finding is the first report of a possible beneficial effect for any candidate esophageal squamous cell carcinoma chemopreventive agent in a randomized controlled trial.

Adult↗
PubMed2005

Pathogenesis and risk factors of small bowel adenocarcinoma: a colorectal cancer sibling?

Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features. The purpose of this article is to review pathogenesis and risks factors of SBA to better understand its molecular features as well as its resemblances and dissimilarities with colorectal cancer (CRC). Better understanding of sporadic and hereditary genetic pathways potentially involved will undoubtedly lead to better prevention and therapeutic management of this rare but aggressive disease.

Adenocarcinoma↗
PubMed2005

Prepregnancy exposure to cigarette smoking and subsequent risk of postmenopausal breast cancer.

OBJECTIVE: To examine the association of cigarette smoking before first pregnancy with risk of postmenopausal breast cancer in a large population-based cohort. PATIENTS AND METHODS: The Iowa Women's Health Study is a prospective cohort study of 55- to 69-year-old women at baseline in 1986. In January 1986, a questionnaire was mailed to 99,826 postmenopausal women to Identify risk factors for cancer and other chronic diseases; 41,836 women responded (42.7% response rate). The primary analyses examined the associations among smoking, parity, age at first birth, and postmenopausal breast cancer. RESULTS: Of the 37,105 women in the cohort at risk, 7095 (19%) and 4186 (11%) initiated smoking before and after first pregnancy, respectively, and 2017 breast cancers were identified before December 31, 1999. Compared with parous women who never smoked, women who began smoking after their first full-term pregnancy were not at increased risk of postmenopausal breast cancer (multivariate-adjusted risk ratio, 1.03; 95% confidence interval, 0.88-1.21). However, women who began smoking before their first pregnancy had a slightly elevated risk of breast cancer (risk ratio, 1.21; 95% confidence Interval, 1.07-1.37). Results were not attenuated by adjustment for age at first pregnancy or number of live births. CONCLUSION: These data suggest that cigarette smoking is associated with a slightly greater risk of postmenopausal breast cancer for women who started smoking before their first full-term pregnancy.

Age Factors↗
PubMed2005

Diabetes mellitus and subsite-specific colorectal cancer risks in the Iowa Women's Health Study.

OBJECTIVE: Controversy remains regarding the association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) risk. To clarify and extend the existing data, we prospectively evaluated the association between self-reported type 2 DM (onset at >30 years of age) and incident CRC, overall and by anatomic subsite, among postmenopausal women in the Iowa Women's Health Study (n = 35,230). METHODS: After 14 years of follow-up, a total of 870 incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up. CRC risks were estimated using Cox proportional hazards regression models. RESULTS: After adjusting for age, body mass index and other potential confounding variables, the relative risk (RR) for women with DM versus women without DM was modestly increased at 1.4 [95% confidence interval (95% CI), 1.1-1.8]. By anatomic subsite, the RR for proximal colon cancer was statistically significantly increased (RR, 1.9; 95% CI, 1.3-2.6), whereas the RRs for distal colon (RR, 1.1; 95% CI, 0.6-1.8) and rectal cancer (RR, 0.8; 95% CI, 0.4-1.6) were not statistically different from unity. Analyses that included DM ascertained at baseline and follow-up yielded similar results. CONCLUSION: In this large, prospective study of postmenopausal women, the association between DM and incident CRC was found to be subsite specific. If confirmed by others, this finding implies that CRC prevention strategies among type 2 DM patients should include examination of the proximal colon.

Age of Onset↗
PubMed2004

Small bowel adenocarcinoma: a rare but aggressive disease.

Unlike the colon and rectum, the small intestine is associated with a very low rate of tumor occurrence. Adenocarcinomas represent the most frequent of these rare digestive tumors and are often fatal as a result of tardy diagnosis. Regardless of the stage, surgery usually remains the cornerstone of small bowel adenocarcinoma therapy. Because of the rarity of the disease, very few significant clinical trials have identified any efficient nonsurgical treatment; however, recent data indicate these tumors might be sensitive to chemotherapy alone or in association with radiation therapy. Conversely, a great deal of progress has been achieved in diagnosis of the tumor, whether by adaptation of existing techniques or development of new ones. We reviewed the clinical aspects of this rare but aggressive disease, focusing on new diagnostic procedures as well as on recent advances in their therapeutic management.

Adenocarcinoma↗
PubMed2003

Cigarette smoking and colorectal cancer: long-term, subsite-specific risks in a cohort study of postmenopausal women.

BACKGROUND & AIMS: Cigarette smoking is a putative risk factor for colorectal cancer (CRC). However, long-term CRC risk estimates among female smokers remain limited and inconsistent. The goal of this prospective study was to assess cigarette smoking and CRC risk, overall and by anatomic subsite, among postmenopausal women. METHODS: Data were drawn from a large population-based cohort (n = 41836) of randomly selected women, age 55-69 years at baseline (Iowa Women's Health Study). Cigarette smoking and other CRC risk factors were characterized at baseline (1986). Incident (n = 869) and fatal (n = 249) CRC cases were identified through December 31, 1999. CRC risks were estimated using Cox proportional hazards regression models. RESULTS: Compared with never smokers, ever smokers had slightly increased risks for both incident (relative risk [RR], 1.17; 95% confidence interval [CI], 1.00-1.36) and fatal (RR, 1.31; 95% CI, 0.98-1.74) CRC in multivariate analyses. Incident CRC risks increased progressively by lengthening induction period (P trend=0.01), reaching a 30% increase (RR, 1.30; 95% CI, 1.04-1.63) after age 45 years. By anatomic subsite, ever smoked cigarettes and induction period were more strongly associated with incident proximal CRC (P = 0.03 and P trend = 0.03, respectively) than incident distal CRC (P=0.44 and P trend=0.10, respectively). CONCLUSIONS: In this long-term cohort study of postmenopausal women, cigarette smoking was positively associated with CRC risk. Onset of smoking in the distant past appeared to confer the greatest risk, especially for incident proximal CRC. These data support a potential subsite-specific role for cigarette smoking in colorectal carcinogenesis, at least among women. Based on emerging data, an epigenetic pathway for smoking-induced CRC is proposed.

Aged↗
PubMed2003

Prospective evaluation of fecal calprotectin as a screening biomarker for colorectal neoplasia.

OBJECTIVES: Stool testing is a well established method of screening for colorectal neoplasia. Emerging data suggest that novel biomarkers may offer performance advantages over fecal occult blood. In this large, prospective study, we assessed fecal calprotectin (a leukocyte-derived protein) as a screening biomarker for colorectal neoplasia. Fecal calprotectin was directly compared to fecal hemoglobin (Hb) and colonoscopy as the existing criterion standards for stool screening and structural evaluation, respectively. METHODS: Subjects included colonoscopy patients with a personal history of colorectal neoplasia, family history of colorectal cancer, or iron deficiency anemia. Stool specimens were collected before purgation, processed appropriately, and quantitatively analyzed for calprotectin (Nycomed Pharma, Oslo, Norway) and for Hb (Mayo Medical Laboratories, Rochester, MN) by masked technicians. Colonoscopies were performed by experienced endoscopists without prior knowledge of the fecal assay results. RESULTS: Among 412 subjects, 97 (24%) subjects had one or more colorectal neoplasms (including three with adenocarcinomas). Fecal calprotectin levels did not differ significantly between subjects with versus subjects without colorectal neoplasms (p = 0.33). Neither tumor number (p = 0.85) nor tumor size (p = 0.86) significantly influenced the observed fecal calprotectin concentrations. Estimates of the sensitivity, specificity, and positive and negative predictive values of fecal calprotectin for any colorectal neoplasms were 37%, 63%, 23%, and 76%, respectively. Comparable performance estimates for fecal Hb were 3%, 97%, 27%, and 77%, respectively. CONCLUSIONS: In this cohort of colonoscopy patients at above average risk, fecal calprotectin was a poor screening biomarker for colorectal neoplasia. Further investigation of tumor-derived, rather than blood-based, biomarkers may be a more rewarding approach to stool screening for colorectal neoplasia.

Aged↗