Clinical Validation of PITX2 DNA Methylation to Predict Outcome in High-Risk Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. Results: The cut-off for the PITX2 methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Conclusions: Early-stage lymph node-positive breast cancer patients with low PITX2 methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high PITX2 DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens

Clinical performance of an analytically validated assay in comparison to microarray technology to assess PITX2 DNA-methylation in breast cancer

Significant evidence has accumulated that DNA-methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene can serve as a prognostic and predictive biomarker in breast cancer. PITX2 DNA-methylation data have been obtained so far from microarray and polymerase chain reaction (PCR)-based research tests. The availability of an analytically validated in vitro methylation-specific real-time PCR assay format (therascreen PITX2 RGQ PCR assay) intended for the determination of the percent methylation ratio (PMR) in the (PITX2) promoter 2 prompted us to investigate whether the clinical performance of these different assay systems generate comparable clinical outcome data. Mathematically converted microarray data of a previous breast cancer study (n = 204) into PMR values leads to a PITX2 cut-off value at PMR 14.73. Recalculation of the data to experimentally equivalent PMRs with the PCR PITX2 assay leads to a cut-off value at PMR 12 with the highest statistical significance. This cut-off predicts outcome of high-risk breast cancer patients to adjuvant anthracycline-based chemotherapy (n = 204; Hazard Ratio 2.48; p < 0.001) comparable to microarray generated results (n = 204; Hazard ratio 2.32; p < 0.0001). The therascreen PITX2 RGQ PCR assay is an analytically validated test with high reliability and robustness and predicts outcome of high-risk breast cancer patients to anthracycline-based chemotherapy

A non-invasive cyberrisk in cooperative driving

This paper presents a hacking risk arising in fully automated cooperative driving. As opposed to common cyber risk scenarios, this scenario does not require internal access to an automated car at all, and is therefore largely independent of current on-board malware protection. A hacker uses a wireless mobile device, for example a hacked smartphone, to send vehicle to- vehicle (V2V) signals from a human-driven car, masquerading it as a fully-automated, cooperating vehicle. It deliberately engages only in high-risk cooperative maneuvers with other cars, in which the unwitting human driver is expected to perform a specific maneuver to avoid collisions with other vehicles. As the human driver is unaware of the planned maneuver, he fails to react as expected by the other vehicles; depending on the situation, a severe collision risk can ensue. We propose a vision-based countermeasure that only requires state-of-the-art equipment for fully-automated vehicles, and assures that such an attack without internal access to an automated car is impossible

General Fail-Safe Emergency Stopping for Highly Automated Vehicles: Paper presented at 9. Tagung Automatisiertes Fahren, München, 21.-22.11.2019

From SAE level 3 onwards, automated vehicles must be able to resolve sudden system failures without driver intervention, including failure modes that are difficult or impossible to address by redundancy alone. Causes of hazardous multiple-point faults—beyond internal failures—include lightning strikes or deliberate attacks by electromagnetic pulses. Stopping the vehicle under such conditions is challenging: A full braking maneuver may risk rear-end collisions or loss of traction; likewise, any other constant braking profile will pose considerable risk of not achieving a true “safe state”. This paper presents an emergency stopping system to execute a situation-dependent braking maneuver that can resolve system failures up to(but not limited to) a full electrics/electronics failure, with the aim of providing a baseline safety solution for all failure modes (short of mechanical failures) for which no dedicated solution is available. The system is composed of an electronic planning unit and a hydraulic/mechanical subsystem, both of which are implemented and tested in simulated and in real environments

Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88

The filamentous fungus Aspergillus niger is widely exploited by the fermentation industry for the production of enzymes and organic acids, particularly citric acid. We sequenced the 33.9-megabase genome of A. niger CBS 513.88, the ancestor of currently used enzyme production strains. A high level of synteny was observed with other aspergilli sequenced. Strong function predictions were made for 6,506 of the 14,165 open reading frames identified. A detailed description of the components of the protein secretion pathway was made and striking differences in the hydrolytic enzyme spectra of aspergilli were observed. A reconstructed metabolic network comprising 1,069 unique reactions illustrates the versatile metabolism of A. niger. Noteworthy is the large number of major facilitator superfamily transporters and fungal zinc binuclear cluster transcription factors, and the presence of putative gene clusters for fumonisin and ochratoxin A synthesis

Search for multi-flare neutrino emissions in 10 yr of IceCube data from a catalog of sources

A recent time-integrated analysis of a catalog of 110 candidate neutrino sources revealed a cumulative neutrino excess in the data collected by IceCube between 2008 April 6 and 2018 July 10. This excess, inconsistent with the background hypothesis in the Northern Hemisphere at the 3.3 sigma level, is associated with four sources: NGC 1068, TXS 0506+056, PKS 1424+240, and GB6 J1542+6129. This Letter presents two time-dependent neutrino emission searches on the same data sample and catalog: a point-source search that looks for the most significant time-dependent source of the catalog by combining space, energy, and time information of the events, and a population test based on binomial statistics that looks for a cumulative time-dependent neutrino excess from a subset of sources. Compared to previous time-dependent searches, these analyses enable a feature to possibly find multiple flares from a single direction with an unbinned maximum-likelihood method. M87 is found to be the most significant time-dependent source of this catalog at the level of 1.7 sigma post-trial, and TXS 0506+056 is the only source for which two flares are reconstructed. The binomial test reports a cumulative time-dependent neutrino excess in the Northern Hemisphere at the level of 3.0 sigma associated with four sources: M87, TXS 0506+056, GB6 J1542+6129, and NGC 1068