Vergleich der diagnostischen Wertigkeit der PSA-Bestimmung mittels der unterschiedlichen Testsysteme Immulite 2000® und Bayer Centaur® und verschiedenen klinischen Entscheidungsalgorithmen einzelner Unterfraktionen des prostataspezifischen Antigens in der Primärdiagnostik des Prostatakarzinoms

Da das Prostatakarzinom mittlerweile der häufigste Tumor der männlichen Bevölkerung darstellt und mit steigender Lebenserwartung zukünftig ein immer größeres Problem in der Gesundheitsversorgung der männlichen Bevölkerung darstellen wird, ist es unerlässlich, Wege zu finden, um dieses Karzinom zuverlässig diagnostizieren zu können. Die Symptome eines Prostatakarzinoms sind nicht immer eindeutig und können auch auf eine benigne Prostatahyperplasie oder eine Prostatitis hindeuten. Es ist also sicherzustellen, dass Patienten ohne ein malignes Geschehen möglichst selten einer invasiven Biopsie unterzogen werden. Die vorliegende Arbeit vergleicht zwei der auf dem Markt angebotenen Testsysteme bezüglich Sensitivität und Spezifität unter Verwendung von 378 Datensätzen eines Patientenkollektivs der urologischen Klinik des Universitätsklinikums Tübingen im Zeitraum Februar bis Dezember 2007. Des Weiteren werden klinische Entscheidungsalgorithmen und allgemein übliche Cut-off Werte kritisch evaluiert. Die Arbeit zeigt, dass eine sinnvolle Kombination der vorliegenden klinischen Werte mit anderen Faktoren, wie dem Patientenalter, durchaus Potential birgt um eine „Übertherapie“ oder unnötige Diagnostik zu vermeiden. Hierbei spielt es per se keine Rolle, welches Testsystem verwendet wird. Es ist wichtiger, die einzelnen „Bausteine“ des entwickelten Entscheidungsbaumes richtig zusammen zu setzen. Zusammenfassend lässt sich sagen, dass der PSA – Test nur bedingt geeignet ist um ein Prostatakarzinom zu diagnostizieren. Es kann nur mit einer Wahrscheinlichkeitsaussage gerechnet werden. Die Kombination verschiedener Untersuchungsmethoden ist zu präferieren. Große Studien der letzten Jahre zeigen allerdings, dass der PSA – Wert in der Verlaufskontrolle einen sehr hohen Stellenwert besitzt und hier ein etablierter und zuverlässiger Parameter ist. In der Primärdiagnostik des Prostatakarzinoms haben andere Marker einen größeren Stellenwert. Diese Marker werden die Anzahl der falsch positiv diagnostizierten Patienten deutlich senken und damit die Anzahl unnötiger Biopsien verringern. Umgekehrt werden sicher auch deutlich weniger falsch negativ diagnostizierte Fälle auftreten, was zu einer weiter sinkenden Sterberate durch das Prostatakarzinom führen wird. Einer der vielversprechendsten Marker zur Diagnostik ist hier sicherlich der PCA3 – Test. Dieser Gentest ermöglicht eine genauere Aussage über die Notwendigkeit einer Biopsie, da das untersuchte Gen karzinomspezifisch ist. Dieser Marker wird das PSA nicht ersetzen, jedoch ist er in der Früherkennung der Erkrankung sicher besser geeignet. Um unnötige Biopsien zu vermeiden, müssen vor allem die Entscheidungsalgorithmen verändert werden und bei Vorliegen des PSA – Wertes anhand des Patientenalters klassifiziert werden. Der entwickelte Entscheidungsbaum kann dabei helfen. Für dessen Erstellung bezog man sich auf die Messwerte des Immulite 2000, da diese rechnerisch höhere Bedeutung in der Diagnostik haben. Die Cut – Off Werte sind ebenso kritisch zu betrachten, da eine Pauschalisierung unnötige Biopsien generiert werden. Als Beispiel kann hier der %fPSA dienen. Liegt dieser bei 15% werden Patienten direkt als nicht – karzinomtragend eingestuft, jedoch zeigen die Analysen dieser Arbeit, dass der optimale Wert bei 13% liegt. Abschließend lässt sich feststellen, dass jedes der Testsysteme seine prädiktiven Vorteile birgt, jedoch gleichzeitig im direkten Vergleich auch Schwächen zeigt. Eine Kombination beider Systeme erscheint sinnvoll. Die differenzierte Betrachtung der einzelnen Unterfraktionen des PSA ist zwingend notwendig

SCIM MILQ: An HPC Quantum Scheduler

With the increasing sophistication and capability of quantum hardware, its integration, and employment in high performance computing (HPC) infrastructure becomes relevant. This opens largely unexplored access models and scheduling questions in such quantum-classical computing environments, going beyond the current cloud access model. SCIM MILQ is a scheduler for quantum tasks in HPC infrastructure. It combines well-established scheduling techniques with methods unique to quantum computing, such as circuit cutting. SCIM MILQ can schedule tasks while minimizing the makespan, i.e., the time that elapses from the start of work to the end, improving on average by 25%. Additionally, it reduces the noise in the circuit by up to 10%, increasing the outcome's reliability. We compare it against an existing baseline and show its viability in an HPC environment.Comment: 9 pages, 2 figures, 3 tables, 1 algorithm, submission to Quantum Week 202

Sub-Cycle Strong-Field Interferometry

A nonlinear interferometry scheme is described theoretically to induce and resolve electron wave- function beating on time scales shorter than the optical cycle of the time-delayed pump and probe pulses. By employing two moderately intense few-cycle laser fields with a stable carrier-envelope phase, a large range of the entire electronic level structure of a quantum system can be retrieved. In contrast to single-photon excitation schemes, the retrieved electronic states include levels that are both dipole- and non-dipole-accessible from the ground electronic state. The results show that strong-field interferometry can reveal both high-resolution and broad-band spectral information at the same time with important consequences for quantum-beat spectroscopy on attosecond or even shorter time scales.Comment: first submitted on April 19, 201

AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease

Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in "low-risk" patients who were potentially eligible for adjuvant treatments or more intensive follow-up. Methods We assembled a cohort of ccRCC patients (n = 443) and identified all "low-risk" patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these "low-risk" patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas. Results Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E-7). Conclusion AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as "low risk" at the time of surgery.Peer reviewe

Expanding the Utilization of Formalin-Fixed, Paraffin-Embedded Archives : Feasibility of miR-Seq for Disease Exploration and Biomarker Development from Biopsies with Clear Cell Renal Cell Carcinoma

Novel predictive tools for clear cell renal cell carcinoma (ccRCC) are urgently needed. MicroRNAs (miRNAs) have been increasingly investigated for their predictive value, and formalin-fixed paraffin-embedded biopsy archives may potentially be a valuable source of miRNA sequencing material, as they remain an underused resource. Core biopsies of both cancerous and adjacent normal tissues were obtained from patients (n = 12) undergoing nephrectomy. After small RNA-seq, several analyses were performed, including classifier evaluation, obesity-related inquiries, survival analysis using publicly available datasets, comparisons to the current literature and ingenuity pathway analyses. In a comparison of tumour vs. normal, 182 miRNAs were found with significant differential expression; miR-155 was of particular interest as it classified all ccRCC samples correctly and correlated well with tumour size (R-2 = 0.83); miR-155 also predicted poor survival with hazard ratios of 2.58 and 1.81 in two different TCGA (The Cancer Genome Atlas) datasets in a univariate model. However, in a multivariate Cox regression analysis including age, sex, cancer stage and histological grade, miR-155 was not a statistically significant survival predictor. In conclusion, formalin-fixed paraffin-embedded biopsy tissues are a viable source of miRNA-sequencing material. Our results further support a role for miR-155 as a promising cancer classifier and potentially as a therapeutic target in ccRCC that merits further investigation.Peer reviewe

A multiomics disease progression signature of low‑risk ccRCC

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Identification of ccRCC likely to progress, despite an apparent low risk at the time of surgery, represents a key clinical issue. From a cohort of adult ccRCC patients (n = 443), we selected low-risk tumors progressing within a 5-years average follow-up (progressors: P, n = 8) and non-progressing (NP) tumors (n = 16). Transcriptome sequencing, miRNA sequencing and proteomics were performed on tissues obtained at surgery. We identified 151 proteins, 1167 mRNAs and 63 miRNAs differentially expressed in P compared to NP low-risk tumors. Pathway analysis demonstrated overrepresentation of proteins related to “LXR/ RXR and FXR/RXR Activation”, “Acute Phase Response Signaling” in NP compared to P samples. Integrating mRNA, miRNA and proteomic data, we developed a 10-component classifier including two proteins, three genes and five miRNAs, effectively differentiating P and NP ccRCC and capturing underlying biological differences, potentially useful to identify “low-risk” patients requiring closer surveillance and treatment adjustments. Key results were validated by immunohistochemistry, qPCR and data from publicly available databases. Our work suggests that LXR, FXR and macrophage activation pathways could be critically involved in the inhibition of the progression of low-risk ccRCC. Furthermore, a 10-component classifier could support an early identification of apparently low-risk ccRCC patients.Peer reviewe

Clear Cell Renal Cell Carcinoma is linked to Epithelial‐to‐Mesenchymal Transition and to Fibrosis

Clear cell renal cell carcinoma (ccRCC) represents the most common type of kidney cancer with high mortality in its advanced stages. Our study aim was to explore the correlation between tumor epithelial‐to‐mesenchymal transition (EMT) and patient survival. Renal biopsies of tumorous and adjacent nontumorous tissue were taken with a 16 g needle from our patients (n = 26) undergoing partial or radical nephrectomy due to ccRCC. RNA sequencing libraries were generated using Illumina TruSeq® Access library preparation protocol and TruSeq Small RNA library preparation kit. Next generation sequencing (NGS) was performed on Illumina HiSeq2500. Comparative analysis of matched sample pairs was done using the Bioconductor Limma/voom R‐package. Liquid chromatography‐tandem mass spectrometry and immunohistochemistry were applied to measure and visualize protein abundance. We detected an increased generic EMT transcript score in ccRCC. Gene expression analysis showed augmented abundance of AXL and MMP14, as well as down‐regulated expression of KL (klotho). Moreover, microRNA analyses demonstrated a positive expression correlation of miR‐34a and its targets MMP14 and AXL. Survival analysis based on a subset of genes from our list EMT‐related genes in a publicly available dataset showed that the EMT genes correlated with ccRCC patient survival. Several of these genes also play a known role in fibrosis. Accordingly, recently published classifiers of solid organ fibrosis correctly identified EMT‐affected tumor samples and were correlated with patient survival. EMT in ccRCC linked to fibrosis is associated with worse survival and may represent a target for novel therapeutic interventions.Peer reviewe

Empirische Religionspädagogik und Praktische Theologie : Metareflexionen, innovative Forschungsmethoden und aktuelle Befunde aus Projekten der Sektion „Empirische Religionspädagogik“ der AKRK

Der Sammelband stellt in insgesamt 20 Beiträgen Metareflexionen, innovative Forschungsmethoden und aktuelle Befunde aus Projekten der AKRK-Sektion "Empirische Religionspädagogik" vor. 19 Autorinnen und Autoren aus verschiedenen Ländern und Sparten der Theologie haben hieran mitgewirkt, auch um weitere empirisch fundierte Forschungsarbeiten anzuregen

Towards a methodical framework for comprehensively assessing forest multifunctionality

Funded by Deutsche Forschungsgemeinschaft. Grant Number: DFG FOR 891/1-3 National Natural Science Foundation of China. Grant Numbers: 30710103907, 30930005, 31170457, 31210103910 Swiss National Science Foundation (SNSF) Sino-German Centre for Research Promotion in Beijing. Grant Number: GZ 986Peer reviewedPublisher PD

A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10(-8)) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P&lt;0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits