Hydroxyapatite growth on anodic TiO2 nanotubes Tsuchiya, Hiroaki; Macak, Jan M.; Müller, Lenka ...
Journal of biomedical materials research. Part A,
1 June 2006, Letnik:
77A, Številka:
3
Journal Article
Low-grade serous ovarian carcinoma (LGSOC) has recently come up as a distinct rare entity of epithelial ovarian cancer. Predictive and prognostic markers are not well studied yet. Because Ki-67 and ...hormone receptors (HR) have been established as relevant cancer biomarkers in several malignant tumors, we evaluated Ki-67 and HR expression rates by immunohistochemistry in 68 patients with LGSOC. We used a standardized cutoff finder algorithm to analyze prognostic significance for overall survival (OS) and progression-free survival (PFS). Cox regression showed a significant continuous decrease in OS for higher proliferation rates with an HR of 1.07% (95% confidence interval, 1.01%-3.67%; P = .048) but not in PFS (P = .86). Cutoff finder analysis revealed the best possible cutoff for OS at 6.28% (P = .04) and for PFS at 1.85% proliferative activity (P = .04). Estrogen receptors (ERs) were expressed in most LGSOC patients (n = 61; 89.7%), progesterone receptor (PR) in about half of patients (n = 33; 48.5%). For both ER/PR, a statistically significant cutoff for PFS could be determined, which was at 75% of positive tumor cells for ER (P = .02) and at 15% of positive tumor cells for PR (P = .03). For OS, HR expression showed a tendency toward better OS for HR-positive tumors but did not turn out statistically significant. Our results show that Ki-67 is a valuable prognostic marker in the subgroup of LGSOC. We could also show that most LGSOCs express HRs but that this expression is associated with a better PFS, a finding valuable in times of antihormonal therapy in LGSOC.
•Ki-67 is an independent prognostic factor for low-grade serous ovarian carcinoma.•Low-grade serous ovarian carcinomas show strong positivity for estrogen receptor.•Low-grade serous ovarian carcinomas show moderate positivity for progesterone receptor.•High hormone receptor expression correlates with a better progression-free survival.•Hormone receptor expression shows only a tendency toward a better overall survival.
Purpose
Precise histological classification of epithelial ovarian cancer (EOC) has immanent diagnostic and therapeutic consequences, but remains challenging in histological routine. The aim of this ...pilot study is to examine the potential of matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry in combination with machine learning methods to classify EOC histological subtypes from tissue microarray.
Experimental design
Formalin‐fixed‐paraffin‐embedded tissue of 20 patients with ovarian clear‐cell, 14 low‐grade serous, 19 high‐grade serous ovarian carcinomas, and 14 serous borderline tumors are analyzed using MALDI‐Imaging. Classifications are computed by linear discriminant analysis (LDA), support vector machines with linear (SVM‐lin) and radial basis function kernels (SVM‐rbf), a neural network (NN), and a convolutional neural network (CNN).
Results
MALDI‐Imaging and machine learning methods result in classification of EOC histotypes with mean accuracy of 80% for LDA, 80% SVM‐lin, 74% SVM‐rbf, 83% NN, and 85% CNN. Based on sensitivity (69–100%) and specificity (90–99%), CCN and NN are most suited to EOC classification.
Conclusion and clinical relevance
The pilot study demonstrates the potential of MALDI‐Imaging derived proteomic classifiers in combination with machine learning algorithms to discriminate EOC histotypes. Applications may support the development of new prognostic parameters in the assessment of EOC.
•A novel sample enrichment method for coproporphyrin (CP) in plasma is proposed.•A robust and sensitive LC–MS method for the detection of coproporphyrin I and III.•A 5-fold increase in CP levels in ...patients whose JNJ-1 plasma level exceeded 20μg/mL.•Coproporphyrin III is unstable in acidified human plasma (pH 3–5).•Plasma samples with <8.5h exposure to daylight can be considered for analysis.
Coproporphyrins are proposed as endogenous biomarkers of hepatic Organic Anion Transporting Polypeptide (OATP)1B functional activity. In this study, a new sample extraction method based on a mixed-mode anion exchange sorbent (SPE clean-up using Oasis 30mg Max 96 well plates) was developed for absolute quantification of coproporphyrin I and III (CP-I and CP-III) in human plasma. Chromatographic separation was performed with an Ace Excel 2 C18 PFP, 3μm, 2.1×150mm, maintained at 60°C. A 10mM ammonium formate containing 0.1% HCOOH and acetonitrile (100%) was used as mobile phase A and B, respectively. Mass transition, m/z 655.3→596.3 was selected to monitor CP-I and CP-III, while m/z 659.3→600.3 transition was used for the stable isotope labelled internal standard. Optimization of the liquid chromatography tandem mass spectrometry method ensured a lower limit of quantification (LLOQ) of 20pg/mL. Both CP-I and CP-III had extraction recoveries of 70%. The calibration range was 0.02–100ng/mL for both CP-I and CP-III, yielding calibration curves with correlation coefficients greater than 0.988. Inter day precision (CV<9%) and accuracy (84.3–103.9%) complied with the recommendation of the European Bioanalytical Forum.
The optimized method was used to analyse plasma samples originating from three independent clinical studies. Obtained CP-I and CP-III plasma baseline levels in healthy volunteers were in good agreement with previously published data. Moreover, CP-I and CP-III plasma levels in human subjects dosed with a clinically confirmed OATP inhibitor were significantly increased compared to their baseline levels. These data demonstrate the potential of CP-I and CP-III as endogenous biomarkers to predict the drug-drug interaction (DDI) related to hepatic OATP1B inhibition. Stability of CP-I and CP-III in plasma and solvents under different processing and storage conditions was also evaluated.
Whole genome sequencing has become fast, accurate, and cheap, paving the way towards the large-scale collection and processing of human genome data. Unfortunately, this dawning genome era does not ...only promise tremendous advances in biomedical research but also causes unprecedented privacy risks for the many. Handling storage and processing of large genome datasets through cloud services greatly aggravates these concerns. Current research efforts thus investigate the use of strong cryptographic methods and protocols to implement privacy-preserving genomic computations.
We propose FHE-BLOOM and PHE-BLOOM, two efficient approaches for genetic disease testing using homomorphically encrypted Bloom filters. Both approaches allow the data owner to securely outsource storage and computation to an untrusted cloud. FHE-BLOOM is fully secure in the semi-honest model while PHE-BLOOM slightly relaxes security guarantees in a trade-off for highly improved performance.
We implement and evaluate both approaches on a large dataset of up to 50 patient genomes each with up to 1000000 variations (single nucleotide polymorphisms). For both implementations, overheads scale linearly in the number of patients and variations, while PHE-BLOOM is faster by at least three orders of magnitude. For example, testing disease susceptibility of 50 patients with 100000 variations requires only a total of 308.31 s (σ=8.73 s) with our first approach and a mere 0.07 s (σ=0.00 s) with the second. We additionally discuss security guarantees of both approaches and their limitations as well as possible extensions towards more complex query types, e.g., fuzzy or range queries.
Both approaches handle practical problem sizes efficiently and are easily parallelized to scale with the elastic resources available in the cloud. The fully homomorphic scheme, FHE-BLOOM, realizes a comprehensive outsourcing to the cloud, while the partially homomorphic scheme, PHE-BLOOM, trades a slight relaxation of security guarantees against performance improvements by at least three orders of magnitude.
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated ...that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10
, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10
, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10
). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid transporter importing very long-chain ...fatty acids (VLCFAs) from the cytosol into peroxisomes for degradation via β-oxidation. ABCD1 deficiency results in accumulation of VLCFAs in tissues and body fluids of X-ALD patients with a wide range of phenotypic manifestations. The most severe variant, cerebral X-ALD (CALD) is characterized by progressive inflammation, loss of the myelin-producing oligodendrocytes and demyelination of the cerebral white matter. Whether the oligodendrocyte loss and demyelination in CALD are caused by a primary cell autonomous defect or injury to oligodendrocytes or by a secondary effect of the inflammatory reaction remains unresolved. To address the role of X-ALD oligodendrocytes in demyelinating pathophysiology, we combined the Abcd1 deficient X-ALD mouse model, in which VLCFAs accumulate without spontaneous demyelination, with the cuprizone model of toxic demyelination. In mice, the copper chelator cuprizone induces reproducible demyelination in the corpus callosum, followed by remyelination upon cuprizone removal. By immunohistochemical analyses of oligodendrocytes, myelin, axonal damage and microglia activation during de-and remyelination, we found that the mature oligodendrocytes of Abcd1 KO mice are more susceptible to cuprizone-induced cell death compared to WT mice in the early demyelinating phase. Furthermore, this effect was mirrored by a greater extent of acute axonal damage during demyelination in the KO mice. Abcd1 deficiency did not affect the function of microglia in either phase of the treatment. Also, the proliferation and differentiation of oligodendrocyte precursor cells and remyelination progressed at similar rates in both genotypes. Taken together, our findings point to an effect of Abcd1 deficiency on mature oligodendrocytes and the oligodendrocyte-axon unit, leading to increased vulnerability in the context of a demyelinating insult.
Congestion control (CC) is an indispensable component of transport protocols to prevent congestion collapse as it distributes the available bandwidth among all competing flows, ideally in a fair ...manner. It thus has a large impact on performance and there exists a constantly evolving set of CC algorithms, each addressing different performance needs. While the algorithms are commonly tested regarding the problems underlying their implementation, the interaction with existing algorithms is often not considered. Additionally considering the fact that content providers (CPs) such as content distribution networks (CDNs) are known to tune TCP stacks for performance gains, the large assortment of algorithms opens the door for custom parametrization and potentially unfair bandwidth sharing. In this paper, we thus empirically investigate if current Internet traffic generated by CPs still adheres to the conventional understanding of fairness. For this, we compare fairness properties of testbed hosts to actual traffic of six major CPs subject to different queue sizes and queueing disciplines in a home-user setting. Additionally, we investigate how mice and elephant flows from the different CPs interact. We find that some employed CC algorithms lead to significantly asymmetric bandwidth shares and very poor flow completion times for mice flows. Fortunately, AQMs such as FQ_CoDel are able to alleviate such unfairness.
•Computer-aided mass transfer parameter determination method.•Sensitivity analysis identifies and evaluates critical operational variables.•Detailed case study exemplifies the pathway of parameter ...determination.•Set of experimental data to compare mass transfer measurements of different authors.
The application of rate-based models incorporating mass and energy transfer phenomena for the design of absorption columns is common practice in chemical industry. These models rely on the high accuracy of mass transfer parameters, i.e. the effective interfacial area aeff as well as the gas and the liquid side mass transfer coefficients kG and kL for gas and liquid phase, which result from experiments at meaningful scale (pilot plant scale). These parameters have a significant impact on the design of the absorption column. Currently, the uncertainty in these mass transfer parameters results in the addition of large safety factors. Hence, a general method comprising a standardised measurement procedure and a standardised computer-aided determination of such parameters has been developed. Physical properties determination together with a sensitivity analysis resulting in an identification and evaluation of critical operational variables has been performed to evaluate their influence on the determination of mass transfer parameters. Within this paper the computer-aided parameter determination method is described in detail. Furthermore, the method is exemplified by a case study.
Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. ...Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.
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