Background and aims
Accurate, long-term risk predictors for colorectal cancer development in patients with sporadic adenomas are lacking. We sought to validate biomarkers predictive of metachronous ...colorectal cancer (mCRC) in patients with sporadic colorectal adenomas, using 374 consecutive patients from a large defined population.
Materials and methods
Risk evaluation was performed for patient and adenoma risk factors (morphometric longest nuclear axis and immunohistochemical markers
survivin
,
human telomerase reverse transcriptase
(
hTERT
),
β-catenin
,
p16INK4a
,
p21CIP1
, and
cyclin D1
). Diagnostic accuracy was assessed by receiver-operating characteristics curve analysis, and uni- and multivariate survival analysis was performed.
Results/findings
Of the 374 patients, 26 (7%) developed mCRC with a median of 5.6 years (range 2–19) from index adenoma. Independent risk factors included age greater than or equal to 60 years, proximal location, multiplicity (greater than or equal to three adenomas), and high-grade neoplasia, with high-grade intraepithelial neoplasia and proximal location as the strongest on multivariate analysis (hazard ratio HR of 4.1 and 5.2, respectively; both
p
< 0.05). The molecular markers hTERT (HR 11.3, 95% confidence interval CI 3.9–33.1;
p
< 0.001) and survivin (HR 7.0, 95% CI 2.4–20.5;
p
< 0.001) were independent predictors for mCRC, and proximal location (4 of 16 = 25% with mCRC) was the only clinical one. The value of hTERT and survivin were retained in the validation set. Survivin and hTERT together yielded high mCRC risk when both were positive (15 of 51 = 29%; HR 14.3, 5.6–36.5), modest with one positive (survivin 4 of 90 = 4.4%; hTERT 4 of 60 = 6.7%), and no risk with both negative (0 of 144 = 0%).
Interpretation/conclusion
hTERT and survivin are the best risk predictors for long-term, mCRC development in patients with sporadic colorectal adenomas.
OBJECTIVEAfter the identification of type 2 diabetes mellitus (T2DM) risk alleles from genome-wide association studies, models have been developed to identify subjects at high risk to develop T2DM. ...We hypothesize that a panel of 20 repeatedly associated T2DM risk alleles influences response to sulfonylureas (SUs).
METHODSTwo hundred and seven incident SU (tolbutamide, glibenclamide, glimepiride, gliclazide) users with T2DM were recruited from four primary care centers. A genetic risk score per patient was calculated based on the number of risk-alleles. With this score, patients were categorized into three predefined genetic risk groups. The effect of the genetic risk group on the achievement of stable SU dose, prescribed stable SU dose, and time to stable SU dose was analyzed.
RESULTSCarriers of more than 17 T2DM risk alleles had a 1.7-fold reduced likelihood to achieve stable SU dose (P=0.044). No significant effect of the number of T2DM risk alleles on prescribed dose was found. Carriers of more than 17 T2DM risk alleles showed a marginally significant increased time to stable dose (hazard ratio0.81; 95% confidence interval, 0.75–1.01, P=0.058).
CONCLUSIONT2DM risk alleles are associated with response to SUs in primary care T2DM patients. This suggests that individualization of T2DM treatment according to genetic profile may be an opportunity to improve clinical outcome.
Abstract
Background
Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may ...improve myocardial perfusion, injury, and function among well-treated PWH.
Methods
Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI.
Results
Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean SD: 0.09 0.56 vs −0.53 0.68 mL/min/g; P = .03) but not CFR by cardiac PET (0.01 0.64 vs −0.07 0.48; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (−13 28 vs 10 26 mL; P = .03) and global circumferential strain (GCS; median interquartile range 25th–75th: −1.3% −2.9%–1.0% vs 2.3% −0.4%–4.1%; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = −0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 0.27 vs −0.05 0.36; P = .04). Eplerenone prevented a small increase in troponin (0.00 −0.13–0.00 vs 0.00 0.00–0.74 ng/L; P = .03) without effects on ECMi (0.9 −2.3–4.3 vs −0.7 −2.2–−0.1 g/m2; P = .38). CD4+ T-cell count (127 −38–286 vs −6 −168–53 cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups.
Conclusions
RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo.
Clinical Trials Registration
NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).
The data suggest beneficial effects of eplerenone to prevent worsening of myocardial perfusion, cardiac function, and myocardial injury among people with HIV without known cardiovascular disease.
Cyclin D1 overexpression, detected by standard immunohistochemistry, was correlated with other prognostic variables and its prognostic value was evaluated in a group of 148 invasive breast cancers ...with long-term follow-up. Overexpression of cyclin D1 (59% of cases) was negatively correlated (chi 2 test) with histological grade (P = 0.0001), mean nuclear area (P = 0.004), mean nuclear volume (P = 0.02), and mitotic activity (P = 0.03) and positively correlated with estrogen receptor (P = 0.0001). There was a strong correlation between cyclin D1 overexpression and histological type (P = 0.0001). Positive cyclin D1 staining was seen in 11 of 13 tubular carcinomas, 3 of 3 mucinous carcinomas, 4 of 4 invasive cribriform carcinomas, and 17 of 20 lobular carcinomas. Of 102 ductal cancers, 52 were positive, and all 6 medullary carcinomas were negative. There were no significant correlations with lymph node status, tumor size, or DNA ploidy. In survival analysis, cyclin D1 overexpression did not provide significant univariate or multivariate prognostic value. In conclusion, cyclin D1 is mainly overexpressed in the well differentiated and lobular types of invasive breast cancer and is strongly associated with estrogen receptor positivity. It is negatively correlated with the proliferation marker mitoses count and with the differentiation markers nuclear area and nuclear volume. However, cyclin D1 overexpression does not seem to have prognostic value in invasive breast cancer when no adjuvant treatment is given.
Obesity is a global epidemic identified as a major risk factor for multiple chronic diseases and, consequently, diet-induced weight loss is used to counter obesity. The adipose tissue is the primary ...tissue affected in diet-induced weight loss, yet the underlying molecular mechanisms and changes are not completely deciphered. In this study, we present a network biology analysis workflow which enables the profiling of the cellular processes affected by weight loss in the subcutaneous adipose tissue. Time series gene expression data from a dietary intervention dataset with two diets was analysed. Differentially expressed genes were used to generate co-expression networks using a method that capitalises on the repeat measurements in the data and finds correlations between gene expression changes over time. Using the network analysis tool Cytoscape, an overlap network of conserved components in the co-expression networks was constructed, clustered on topology to find densely correlated genes, and analysed using Gene Ontology enrichment analysis. We found five clusters involved in key metabolic processes, but also adipose tissue development and tissue remodelling processes were enriched. In conclusion, we present a flexible network biology workflow for finding important processes and relevant genes associated with weight loss, using a time series co-expression network approach that is robust towards the high inter-individual variation in humans.
Abstract Objectives To determine the prevalence of registered trials and to evaluate the risk of bias between registered and unregistered clinical trials. Study Design and Setting The Cochrane ...Gynecology and Fertility Group's specialized register was searched on November 5, 2015, for randomized controlled trials published from 2010 to 2014. Studies were selected if they had randomized women or men for fertility treatments, were published in full text and written in English. Two reviewers then independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. Results Of 693 eligible randomized controlled trials, only 44% were found to be registered. Unregistered clinical trials had smaller sample sizes than registered trials ( P < 0.001). A random subsample of 125 registered and 125 unregistered trials was assessed for risk of bias using five of the Cochrane Risk of Bias “domains.” Registered and unregistered trials differed in their risk of bias for random sequence generation ( P = 0.001), allocation concealment ( P = 0.003), and selective reporting ( P < 0.001) but not blinding or incomplete outcome data ( P > 0.05) domains. Only 54 (43.2%) of the 125 registered trials were registered prospectively. This study has the following limitations. Only English language trials were included in this review. We were unable to obtain protocols for the unregistered trials and therefore were unable to assess the risk of bias in the selective reporting domain. Conclusions All available trials should be included in systematic reviews and assessed for risk of bias as there are both registered trials with high risk of bias and unregistered trials with low risk of bias and by excluding unregistered trials more than half of the available evidence will be lost.
Increased protein intake versus maltodextrin intake for 4 weeks lowers blood pressure. Concerns exist that high‐protein diets reduce renal function. Effects of acute and 4‐week protein intake versus ...maltodextrin intake on renal acid load, glomerular filtration rate and related parameters were compared in this study. Seventy‐nine overweight individuals with untreated elevated blood pressure and normal kidney function were randomized to consume a mix of protein isolates (60 g/day) or maltodextrin (60 g/day) for 4 weeks in energy balance. Twenty‐four‐hour urinary potential renal acid load (uPRAL) was compared between groups. A subgroup (maltodextrin N = 27, protein mix N = 25) participated in extra test days investigating fasting levels and postprandial effects of meals supplemented with a moderate protein‐ or maltodextrin‐load on glomerular filtration rate, effective renal plasma flow, plasma renin, aldosterone, pH, and bicarbonate. uPRAL was significantly higher in the protein group after 4 weeks (P ≤ 0.001). Postprandial filtration fraction decreased further after the protein‐supplemented breakfast than after the maltodextrin‐supplemented breakfast after 4 weeks of supplementation (P ≤ 0.001). Fasting and postprandial levels of glomerular filtration rate, effective renal plasma flow, renin, aldosterone, angiotensin‐converting enzyme, pH and bicarbonate did not differ between groups. In conclusion, 4 weeks on an increased protein diet (25% of energy intake) increased renal acid load, but did not affect renal function. Postprandial changes, except for filtration fraction, also did not differ between groups. These data suggest that a moderate increase in protein intake by consumption of a protein mix for 4 weeks causes no (undesirable) effects on kidney function in overweight and obese individuals with normal kidney function.
An increased protein diet (25% of energy intake) for 4 weeks had no effect on fasting renal function despite an increased renal acid load compared to a diet containing 15% of energy in the form of protein. Postprandial changes, except for filtration fraction, also did not differ between diets. These data suggest that consumption of a protein mix for 4 weeks causes no harm for the kidneys.
Background & Aims: Current models of colorectal adenoma to carcinoma progression do not fully reflect the genetic heterogeneity and complexity of the disease. The aim of the present study was to ...identify genetic changes discriminating adenomas that have progressed to carcinoma from adenomas that have not progressed, and to refine the current genetic models of colorectal adenoma to carcinoma progression, based on a genome-wide analysis of chromosomal aberrations. Methods: Sixty-six nonprogressed colorectal adenomas, 46 progressed adenomas (malignant polyps), and 36 colorectal carcinomas were screened for chromosomal aberrations by comparative genomic hybridization, and for mutations in the adenomatous polyposis coli (APC) and K-ras gene. Data analysis focused on cancer-associated genetic changes in adenomas. Results: Accumulation of losses in 8p21-pter, 15q11-q21, 17p12-13, and 18q12-21, and gains in 8q23-qter, 13q14-31, and 20q13 were strongly associated with adenoma-to-carcinoma progression, independent of the degree of dysplasia. Hierarchic cluster analysis demonstrated the presence of 3 distinct subgroups of adenomas, characterized by unique combinations of genetic aberrations in the adenomas (17p loss and K-ras mutation, 8q and 13q gain, and 18q loss and 20q gain, respectively). Conclusions: The presence of 2 or more of the aforementioned 7 chromosomal changes was associated with progressed colorectal adenomas and colorectal cancer. In addition, evidence was found that these chromosomal abnormalities occurred in specific combinations of a few abnormalities rather than as a mere accumulation of events, indicating the existence of multiple independent chromosomal instability pathways of colorectal cancer progression.
GASTROENTEROLOGY 2002;123:1109-1119
The efficacy of low-calorie diets (LCDs) has not been investigated in large-scale studies or among people from different regions, who are perhaps unaccustomed to such methods of losing weight. The ...aim of the present study was to investigate changes in obesity measures among overweight/obese adults from eight European cities (from Northern, Central and Southern Europe) during the 8-week LCD phase of the DiOGenes study (2006-2007), a family-based, randomised, controlled dietary intervention.
938 overweight/obese adults completed baseline examinations and underwent an 8-week LCD, providing 3.3-4.2 MJ/day to replace all meals. Anthropometric measurements and body composition were assessed at baseline and post-LCD.
773 (82.4%) adults (mean age, 43.1 y) completed the LCD successfully. The highest drop-out rate was observed in Southern (24.9%) and the lowest in Northern (13.3%) European cities. Overall, the LCD induced favourable changes in all outcomes, including an approximate 11.0% reduction in body weight and body fat percentage. Changes in outcomes differed significantly between regions, with North- and Central-European cities generally achieving higher percentage reductions in most anthropometric measurements assessed. Nonetheless, participants in Southern Europe reduced their body fat percentage significantly more than participants in Northern Europe (-11.8 vs. -9.5%, P = 0.017).
The LCD significantly improved anthropometric and body composition measurements in all cities participating in DiOGenes.
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