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result(s) for
"van Iterson, M"
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Gene Expression Differences in Prostate Cancers between Young and Old Men
Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort. Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence. Our results provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men.
Journal Article
Relative power and sample size analysis on gene expression profiling data
Background
With the increasing number of expression profiling technologies, researchers today are confronted with choosing the technology that has sufficient power with minimal sample size, in order to reduce cost and time. These depend on data variability, partly determined by sample type, preparation and processing. Objective measures that help experimental design, given own pilot data, are thus fundamental.
Results
Relative power and sample size analysis were performed on two distinct data sets. The first set consisted of Affymetrix array data derived from a nutrigenomics experiment in which weak, intermediate and strong PPAR
α
agonists were administered to wild-type and PPAR
α
-null mice. Our analysis confirms the hierarchy of PPAR
α
-activating compounds previously reported and the general idea that larger effect sizes positively contribute to the average power of the experiment. A simulation experiment was performed that mimicked the effect sizes seen in the first data set. The relative power was predicted but the estimates were slightly conservative. The second, more challenging, data set describes a microarray platform comparison study using hippocampal
δ
C-doublecortin-like kinase transgenic mice that were compared to wild-type mice, which was combined with results from Solexa/Illumina deep sequencing runs. As expected, the choice of technology greatly influences the performance of the experiment. Solexa/Illumina deep sequencing has the highest overall power followed by the microarray platforms Agilent and Affymetrix. Interestingly, Solexa/Illumina deep sequencing displays comparable power across all intensity ranges, in contrast with microarray platforms that have decreased power in the low intensity range due to background noise. This means that deep sequencing technology is especially more powerful in detecting differences in the low intensity range, compared to microarray platforms.
Conclusion
Power and sample size analysis based on pilot data give valuable information on the performance of the experiment and can thereby guide further decisions on experimental design. Solexa/Illumina deep sequencing is the technology of choice if interest lies in genes expressed in the low-intensity range. Researchers can get guidance on experimental design using our approach on their own pilot data implemented as a BioConductor package, SSPA
http://bioconductor.org/packages/release/bioc/html/SSPA.html
.
Journal Article
Effects of Thoracic Epidural Anaesthesia on the Serosal Microcirculation of the Human Small Intestine
Background
The effect of thoracic epidural analgesia (TEA) on splanchnic blood flow during abdominal surgery remains unclear. The purpose of this study was to examine whether the hemodynamic effects of TEA resulted in microcirculatory alterations to the intestinal serosa, which was visualized using incident dark-field (IDF) videomicroscopy.
Methods
An observational cohort study was performed. In 18 patients, the microcirculation of the intestinal serosa was visualized with IDF. Microcirculatory and hemodynamic measurements were performed prior to (T1) and after administering a bolus of levobupivacaine (T2). If correction of blood pressure was indicated, a third measurement was performed (T3). The following microcirculatory parameters were calculated: microvascular flow index, proportion of perfused vessels, perfused vessel density and total vessel density. Data are presented as median [IQR].
Results
Mean arterial pressure decreased from 73 mmHg (68–83) at T1 to 63 mmHg (±11) at T2 (
p
= 0.001) with a systolic blood pressure of 114 mmHg (98–128) and 87 (81–97), respectively (
p
= 0.001). The microcirculatory parameters of the bowel serosa, however, were unaltered. In seven patients, blood pressure was corrected to baseline values from a MAP of 56 mmHg (55–57), while microcirculatory parameters remained constant.
Conclusion
We examined the effects of TEA on the intestinal serosal microcirculation during abdominal surgery using IDF imaging for the first time in patients. Regardless of a marked decrease in hemodynamics, microcirculatory parameters of the bowel serosa were not significantly affected.
Trial registry number
ClinicalTrials.gov identifier NCT02688946.
Journal Article
Can sidestream dark field (SDF) imaging identify subtle microvascular changes of the bowel during colorectal surgery?
Background
Recognition of a non-viable bowel during colorectal surgery is a challenging task for surgeons. Identifying the turning point in serosal microcirculatory deterioration leading up to a non-viable bowel is crucial. The aim of the present study was to determine whether sidestream darkfield (SDF) imaging can detect subtle changes in serosal microcirculation of the sigmoid after vascular transection during colorectal surgery.
Methods
A prospective observational clinical study was performed at a single medical centre. All eligible participants underwent laparoscopic sigmoid resection and measurements were taken during the extra-abdominal phase. Microcirculation was measured at the transected bowel and 20 cm proximal to this point. Microcirculatory parameters such as Microvascular Flow Index (MFI), proportion of perfused vessels (PPV), perfused vessel density (PVD), total vessel density (TVD) and the Heterogeneity Index were determined. Data are presented as median (interquartile range) or mean ± standard deviation.
Results
A total of 60 SDF images were acquired for 10 patients. Perfusion parameters and perfused vessel density were significantly lower at the transected bowel compared with the non-transected measurements [MFI 2.29 (1.96–2.63) vs 2.96 (2.73–3.00),
p
= 0.007; PPV 74% (55–83) vs 94% (86–97),
p
= 0.007; and PVD 7.61 ± 2.99 mm/mm
2
versus 10.67 ± 1.48 mm/mm
2
,
p
= 0.009]. Total vessel density was similar between the measurement locations.
Conclusions
SDF imaging can identify changes of the bowel serosal microcirculation. Significantly lower serosal microcirculatory parameters of the vascular transected bowel was seen compared with the non-transected bowel. The ability of SDF imaging to detect subtle differences holds promise for future research on microvascular cut-off values leading to a non-viable bowel.
Journal Article
Single Molecule Sequencing of Free DNA from Maternal Plasma for Noninvasive Trisomy 21 Detection
Noninvasive fetal aneuploidy detection by use of free DNA from maternal plasma has recently been shown to be achievable by whole genome shotgun sequencing. The high-throughput next-generation sequencing platforms previously tested use a PCR step during sample preparation, which results in amplification bias in GC-rich areas of the human genome. To eliminate this bias, and thereby experimental noise, we have used single molecule sequencing as an alternative method.
For noninvasive trisomy 21 detection, we performed single molecule sequencing on the Helicos platform using free DNA isolated from maternal plasma from 9 weeks of gestation onwards. Relative sequence tag density ratios were calculated and results were directly compared to the previously described Illumina GAII platform.
Sequence data generated without an amplification step show no GC bias. Therefore, with the use of single molecule sequencing all trisomy 21 fetuses could be distinguished more clearly from euploid fetuses.
This study shows for the first time that single molecule sequencing is an attractive and easy to use alternative for reliable noninvasive fetal aneuploidy detection in diagnostics. With this approach, previously described experimental noise associated with PCR amplification, such as GC bias, can be overcome.
Journal Article
Systemic haemodynamics and oxygenation during haemodilution in children
Summary
Transfusion of homologous blood should be avoided when possible, and one technique that diminishes perioperative requirement for donor blood is haemodilution. In children its effects on systemic haemodynamics and systemic oxygenation have not been reported. Six children aged 4-12 yr were anaesthetised for major surgery and blood was withdrawn to reduce packed cell volume to 25%.
Cardiac index increased from 3·1 (SD 0·5) L min
-1 m
-2 at baseline to 4·4 (0·5) L min
-1 m
-2 at the end of surgery, when packed cell volume was 16 (1)%; this change, compensating for the decline in oxygen carrying capacity, was associated with a fall in systemic vascular resistance and a rise in stroke volume. Oxygen extraction from haemoglobin rose from 0·22 (0·05) to 0·33 (0·06). Perioperative blood loss was 40% of circulating blood volume; however, owing to reinfusion of autologous blood (and use of a cell saver in three patients), the haemoglobin one day after operation was only 19% lower than preoperatively (9·9 [1·5] vs 12·5 [2·5] g/dL).
In this study, children seemed at least as able as adults to compensate for the effects of haemodilution, which allowed major surgery without transfusion of homologous blood.
Journal Article
Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution
Association studies on omic-level data other then genotypes (GWAS) are becoming increasingly common, i.e., epigenome- and transcriptome-wide association studies (EWAS/TWAS). However, a tool box for the analysis of EWAS and TWAS studies is largely lacking and often approaches from GWAS are applied despite the fact that epigenome and transcriptome data have very different characteristics than genotypes. Here, we show that EWASs and TWASs are prone not only to significant inflation but also bias of the test statistics and that these are not properly addressed by GWAS-based methodology (i.e. genomic control) and state-of-the-art approaches to control for unmeasured confounding (i.e. RUV, sva and cate). We developed a novel approach that is based on the estimation of the empirical null distribution using Bayesian statistics. Using simulation studies and empirical data, we demonstrate that our approach maximizes power while properly controlling the false positive rate. Finally, we illustrate the utility of our method in the application of meta-analysis by performing EWASs and TWASs on age and smoking which highlighted an overlap in differential methylation and expression of associated genes. An implementation of our new method is available from http://bioconductor.org/packages/bacon/ .
Paper
Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution
We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking.
Journal Article