Mexican Americans have a high prevalence of diabetes and burden of diabetes-related complications, highlighting the need for novel preventive strategies and noninvasive predictors of diabetes risk ...tailored to this population. Changes in the gut microbiome have the potential to predict diabetes. Here, we aimed to identify alterations in the gut microbiome associated with diabetes in the high-risk population of Mexican Americans in South Texas. Stool samples were collected from 216 subjects from the population-based Cameron County Hispanic Cohort. Among them, 75 had type 2 diabetes. Taxonomic and functional profiling of the stool samples were assessed by 16S and shotgun metagenomic sequencing, and the influence of genetic factors was explored. The gut microbiome of subjects with diabetes was enriched with proinflammatory Proteobacteria members (Enterobacteriaceae, Escherichia
Shigella) and depleted of butyrate-producing Clostridiales members (Faecalibacterium prausnitzii, Peptostreptococcaceae, and Clostridium
1). The accompanying metagenomic changes in subjects with diabetes suggested dysregulated amino acid metabolism, reduced galacturonate and glucuronate catabolism (correlating with Faecalibacterium prausnitzii abundance), and enriched heme biosynthesis (correlating with
abundance). Polymorphism rs7129790 near
was strongly associated with high
abundance and was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. In conclusion, Mexican Americans in South Texas with diabetes display distinct gut microbiome and metagenomic signatures. These signatures may have utility in risk modeling and disease prevention in this high-risk population.
The gut microbiome composition varies across ethnicities and geographical locations, yet studies on diabetes-associated microbiome changes specific to high-risk Mexican Americans are lacking. Here, we aimed to identify specific alterations associated with diabetes in this population, as well as host genetic factors that may explain increased disease susceptibility in this ethnic group. Using samples from a population-based cohort of Mexican Americans with a high prevalence of obesity and diabetes, we confirmed findings from studies on other ethnicities that suggested promotion of a chronic proinflammatory environment, loss of butyrate production, and compromised intestinal barrier integrity. High abundance of proinflammatory
was associated with a polymorphism that was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. Validation of microbiome-based risk models for diabetes should be evaluated in prospective cohort studies.
Chemoprevention – History and general principles Wu, Xiangwei, PhD; Patterson, Sherri; Hawk, Ernest, MD MPH
Baillière's best practice & research. Clinical gastroenterology,
08/2011, Letnik:
25, Številka:
4
Journal Article
Recenzirano
Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its ...population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.
Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk.
The Adenoma Prevention With Celecoxib (APC) trial ...studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval CI, 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies).
Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.
Barrett's esophagus is the precursor lesion of esophageal adenocarcinoma, whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective ...interpretation of histologic grading in predicting Barrett's esophagus progression call for more objective biomarkers that can improve risk prediction. We conducted a genome-wide profiling of 754 human microRNAs (miRNA) in 35 normal epithelium, 34 Barrett's esophagus, and 36 esophageal adenocarcinoma tissues using TaqMan real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: normal epithelium versus Barrett's esophagus/esophageal adenocarcinoma tissues. Moreover, there was an excellent clustering of Barrett's metaplasia (without dysplasia) tissues from normal epithelium tissues. However, Barrett's esophagus tissues of different stages and esophageal adenocarcinoma tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in Barrett's esophagus and esophageal adenocarcinoma tissues, with the most dramatic alterations occurring at the Barrett's metaplasia stage. Known oncomiRs, such as miR-21, miR-25, and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from Barrett's esophagus to esophageal adenocarcinoma. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to esophageal adenocarcinoma but not Barrett's esophagus included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for esophageal adenocarcinoma development.
The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal ...mutations in
have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal
and driver
mutations, thus challenging the prevailing monoclonal monocryptal model.
High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of
and
was performed using nanofluidic PCRs in matched bulk biopsies (
= 59) and crypts (
= 591) from 18 adenomas and seven carcinomas and adjacent normal tissues.
Multiple co-occurring truncal
and driver
alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected
mutations that were prominent among carcinomas, whereas abundant wild-type
crypts were detected in adenomas.
mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed.
The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis.
.
The Wnt/β-catenin signaling pathway plays a key role in stem cell maintenance in the colorectum. Rare high-penetrance genetic mutations in components of this pathway result in familial colorectal ...cancer, yet the impact of common, germline variants remains unknown.
We assessed 172 variants in 26 genes from the Wnt/β-catenin pathway in 809 colorectal cancer cases and 814 healthy controls, followed by replication of the top findings in another 691 cases and 775 controls. In silico informatic tools were used to predict functional effects of variants.
Eighteen SNPs in the pathway were significantly associated with colorectal cancer risk (P < 0.05) in the discovery phase. We observed a significant dose-response increase in colorectal cancer risk by number of risk genotypes carried (P = 4.19 × 10(-8)). Gene-based analysis implicated CSNK1D (P = 0.014), FZD3 (P = 0.023), and APC (P = 0.027) as significant for colorectal cancer risk. In the replication phase, FZD3:rs11775139 remained significantly associated with reduced risk with a pooled OR of 0.85 95% confidence interval (CI), 0.76-0.94, P = 0.001. Although borderline significant in the replication population, APC:rs2545162 was highly significant in the pooled analysis-OR, 1.42; 95% CI, 1.16-1.74; P = 0.00085. Functional assessment identified several potential biologic mechanisms underlying these associations.
Our findings suggest that common germline variants in the Wnt/β-catenin pathway may be involved in colorectal cancer development.
These variants may be informative in colorectal cancer risk assessment to identify individuals at increased risk who would be candidates for screening.
Background
Optimal hepatitis C virus (HCV) screening strategies for cancer patients have not been established. We compared the performance of selective HCV screening strategies.
Methods
We surveyed ...patients presenting for first systemic anticancer therapy during 2013–2014 for HCV risk factors. We estimated the prevalence of positivity for HCV antibody (anti-HCV) and examined factors associated with anti-HCV status using Fisher’s exact test or Student’s
t
test. Sensitivity was calculated for screening patients born during 1945–1965, patients with ≥ 1 other risk factor, or both cohorts (“combined screening”).
Results
We enrolled 2122 participants. Median age was 59 years (range, 18–91); 1138 participants were women. Race/ethnicity distribution was white non-Hispanic, 76% (
n
= 1616); Hispanic, 11% (
n
= 233); black non-Hispanic, 8% (
n
= 160); Asian, 4% (
n
= 78); and other, 2% (
n
= 35). Primary cancer distribution was non-liver solid tumor, 78% (
n
= 1664); hematologic cancer, 20% (
n
= 422); and liver cancer, 1% (
n
= 28). Prevalence of anti-HCV was 1.93% (95% CI, 1.39%–2.61%). Over 28% of patients with detectable HCV RNA were unaware of infection. Factors significantly associated with anti-HCV positivity included less than a bachelor’s degree, birth in 1945–1965, chronic liver disease, injection drug use, and blood transfusion or organ transplant before 1992. A total of 1315 participants (62%), including 39 of 41 with anti-HCV, reported ≥ 1 risk factor. Sensitivity was 80% (95% CI, 65–91%) for birth-cohort-based, 68% (95% CI, 52–82%) for other-risk-factor-based, and 95% (95% 83–99%) for combined screening.
Conclusion
Combined screening still missed 5% of patients with anti-HCV. These findings favor universal HCV screening to identify all HCV-infected cancer patients.
ObjectiveCancer care providers’ (CCPs) attitudes towards smoking cessation are influenced by many factors, including their smoking status and knowledge. Our objective was to assess CCPs’ ...characteristics, tobacco use and smoking cessation practices in two Latin American cancer centres.DesignCross-sectional survey.SettingsTwo urban cancer centres located in Colombia and Mexico.ParticipantsA total of 238 CCPs.MeasuresOnline survey consisted of 28 close-ended questions adapted from the 2012 International Association for the Study of Lung Cancer survey and the Global Adult Tobacco Survey developed by the WHO. Means, frequencies and proportions were reported for each country. Factors associated to providing of smoking cessation treatment or referral at initial visit were evaluated using logistic regression.ResultsCurrent smoking prevalence was 10.5% and 12.3% among Colombian and Mexican CCPs, respectively. Around three quarters of the Colombian (86.4%) and Mexican CCPs (66.1%) considered to have inadequate training in smoking cessation. Approximately two-thirds of Colombian (67.5%) and Mexican CCPs (63.9%) reported always or most of the time asking patients about tobacco use during the initial visit. In Colombia and Mexico, the most relevant barriers for providing cessation services were (1) difficulties for motivating patients with cancer, (2) patient resistance in quitting smoking, (3) lack of local resources or referral centres for smoking cessation and (4) lack of training in smoking cessation. CCPs appointed at Instituto Nacional de Cancerología were less likely to provide cessation treatment or referral to their patients if they had less than 50% of their time devoted to patient care and were former or current smokers. The regression model for Instituto de Cancerología did not retain statistically significant variables.ConclusionOur findings highlight an urgent need for assisting Latin American CCPs in their quitting efforts as well as expanding formal smoking cessation training specifically tailored to these professionals for improving patients’ cancer prognosis and quality of life.
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