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Purpose: In this prospective exploratory study, we evaluated the feasibility of [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET/MRI-based chemotherapy response prediction in pancreatic ductal adenocarcinoma at two weeks upon therapy onset. Material and methods: In a mixed cohort, seventeen patients treated with chemotherapy in neoadjuvant or palliative intent were enrolled. All patients were imaged by [¹⁸F]FDG PET/MRI before and two weeks after onset of chemotherapy. Response per RECIST1.1 was then assessed at 3 months [¹⁸F]FDG PET/MRI-derived parameters (MTV₅₀%, TLG₅₀%, MTV₂.₅, TLG₂.₅, SUVmₐₓ, SUVpₑₐk, ADCmₐₓ, ADCmₑₐn and ADCmin) were assessed, using multiple t-test, Man–Whitney-U test and Fisher’s exact test for binary features. Results: At 72 ± 43 days, twelve patients were classified as responders and five patients as non-responders. An increase in ∆MTV₅₀% and ∆ADC (≥ 20% and 15%, respectively) and a decrease in ∆TLG₅₀% (≤ 20%) at 2 weeks after chemotherapy onset enabled prediction of responders and non-responders, respectively. Parameter combinations (∆TLG₅₀% and ∆ADCmₐₓ or ∆MTV₅₀% and ∆ADCmₐₓ) further improved discrimination. Conclusion: Multiparametric [¹⁸F]FDG PET/MRI-derived parameters, in particular indicators of a change in tumor glycolysis and cellularity, may enable very early chemotherapy response prediction. Further prospective studies in larger patient cohorts are recommended to their clinical impact. CA Extern

Interferon beta (IFNβ) triggers the JAK-STAT signaling cascade to induce IFN-stimulated genes (ISGs), which is a hallmark of innate immune response against viral infections. The transcription factors STAT1 and STAT2 become activated and, together with IRF9, assemble into the ISGF3 complex. This complex translocates to the nucleus and activates ISGs by binding to its DNA recognition motif. Most cell types have the potential to activate ISGs upon IFNs signaling but embryonic stem cells (ESC) have a very different response compared to differentiated cells. However, the exact molecular mechanisms that drive this cell type specific interferon signaling are poorly characterized. In this thesis, the cell type specific IFNβ response was compared between mouse ESCs and differentiated cells like mouse embryonic fibroblasts (MEFs) that carry the same genome. I tested the hypothesis that the cell type specific differences in IFNβ response originate from distinct epigenetic states by applying a genome-wide multiomics approach: (i) A differential gene expression analysis by RNA-seq of IFNβ stimulation defined a total of 513 ISGs and allowed it to identify cell type specific ISG signatures. The bulk sequencing analysis was complemented with single cell RNA-seq to resolve heterogeneity of gene expression response. (ii) By TF chromatin immunoprecipitation followed by sequencing (ChIP-seq) the STAT1 and STAT2 binding sites were mapped across cell types. (iii) Active chromatin regions were detected with the assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq). Single cell ATAC-seq was used to identify coregulated enhancers and promoters. (iv) ChIP-seq of histone acetylation (ac) and mono- and tri-methylation (me1, me3) marks at histone lysine residues for H3K4me1, H3K4me3, H3K9ac, H3K27ac, H3K9me3 and H3K27me3 was conducted. The analysis of this comprehensive data set yielded cell type specific patterns of ISGs, ISGF3 binding and chromatin features. The overall stronger IFNβ response in MEFs could be rationalized by factors from the JAK/STAT signaling cascade being constitutively more strongly expressed. In addition, 33 ISGs in ESCs and 305 ISGs in MEFs were found to be cell type specific and thus candidates for epigenetic regulation. To characterize the underlying mechanism, the genomic location, chromatin context and target genes of ISGF3 were characterized. While 92 ISGF3 sites were shared between ESCs and MEFs, 116 and 184 sites were specific for one cell type and found at promoters and putative enhancers. Based on a co-regulation analysis of single cell ATAC-seq data, many of these enhancers could be linked to specific ISGs. Furthermore, the analysis revealed that a pre-existing enrichment of H3K4me1 and open chromatin loci at ISGF3 sites was positively correlated with ISGF3 binding while H3K27me3 showed the opposite effect. In summary, this thesis characterizes the contribution of epigenetic gene regulation mechanisms to the cell type specific IFNβ response and rationalizes how chromatin features direct cell type specific ISGF3 binding. The insight gained opens up new possibilities for targeted interference with interferon response in anti-viral drug development by accounting for the contribution of chromatin to this process.

A sensor system capable of supporting automated driving functions needs to provide both reliable localization of the vehicle and robust environment perception of the vehicle's surrounding. The following chapter introduces the working principles and the state of the art of automotive sensors for localization (GNSS and INS) and environment perception (camera, radar and LIDAR), corresponding sensormodels and sensor fusion techniques. Sensor models will allow for the replacement of conventional test drives and physical component tests by using simulations in virtual test environments to meet the increasing requirements of automated vehicles with respect to development costs, time and safety. Considering the multitude and complexity of possible environmental conditions, realistic simulation of perception sensors is a particularly demanding topic. To increase the performance of a sensor system, compensate for limitations of each sensor modality, and increase the overall robustness of the system, sensor fusion techniques are an important subject in automotive research.

Here we present an experimental model for human luminal progenitor cells that enables single, primary cells isolated from normal tissue to generate complex branched structures resembling the ductal morphology of low-grade carcinoma of no special type. Thereby, we find that ductal structures are generated through invasive branching morphogenesis via matrix remodeling and identify reduced actomyosin contractility as a prerequisite for invasion. In addition, we show that knockout of E-cadherin causes a dissolution of duct formation as observed in invasive lobular carcinoma, a subtype of invasive carcinomas where E-cadherin function is frequently lost. Thus, our model shows that invasive capacity can be elicited from normal luminal cells in specific environments, which results in low-grade no special type morphology. This assay offers a platform to investigate the dynamics of luminal cell invasion and unravel the impact of genetic and non-genetic aberrations on invasive morphology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

In schizophrenia, neurocognitive subtypes can be distinguished based on cognitive performance and they are associated with neuroanatomical alterations. We investigated the existence of cognitive subtypes in shortly medicated recent onset psychosis patients, their underlying gray matter volume patterns and clinical characteristics. We used a K-means algorithm to cluster 108 psychosis patients from the multi-site EU PRONIA (Prognostic tools for early psychosis management) study based on cognitive performance and validated the solution independently (N = 53). Cognitive subgroups and healthy controls (HC; n = 195) were classified based on gray matter volume (GMV) using Support Vector Machine classification. A cognitively spared (N = 67) and impaired (N = 41) subgroup were revealed and partially independently validated (Nspared = 40, Nimpaired = 13). Impaired patients showed significantly increased negative symptomatology (pfdr = 0.003), reduced cognitive performance (pfdr pfdr p = 0.01) separating impaired patients from HC revealed increases and decreases across several fronto-temporal-parietal brain areas, including basal ganglia and cerebellum. Cognitive and functional disturbances alongside brain morphological changes in the impaired subgroup are consistent with a neurodevelopmental origin of psychosis. Our findings emphasize the relevance of tailored intervention early in the course of psychosis for patients suffering from the likely stronger neurodevelopmental character of the disease.

Perception sensors such as camera, radar, and lidar have gained considerable popularity in the automotive industry in recent years. In order to reach the next step towards automated driving it is necessary to implement fault diagnosis systems together with suitable mitigation solutions in automotive perception sensors. This is a crucial prerequisite, since the quality of an automated driving function strongly depends on the reliability of the perception data, especially under adverse conditions. This publication presents a systematic review on faults and suitable detection and recovery methods for automotive perception sensors and suggests a corresponding classification schema. A systematic literature analysis has been performed with focus on lidar in order to review the state-of-the-art and identify promising research opportunities. Faults related to adverse weather conditions have been studied the most, but often without providing suitable recovery methods. Issues related to sensor attachment and mechanical damage of the sensor cover were studied very little and provide opportunities for future research. Algorithms, which use the data stream of a single sensor, proofed to be a viable solution for both fault detection and recovery.

To bridge the translational gap between recent discoveries of distinct molecular phenotypes of pancreatic cancer and tangible improvements in patient outcome, there is an urgent need to develop strategies and tools informing and improving the clinical decision process. Radiomics and machine learning approaches can offer non-invasive whole tumor analytics for clinical imaging data-based classification. The retrospective study assessed baseline computed tomography (CT) from 207 patients with proven pancreatic ductal adenocarcinoma (PDAC). Following expert level manual annotation, Pyradiomics was used for the extraction of 1474 radiomic features. The molecular tumor subtype was defined by immunohistochemical staining for KRT81 and HNF1a as quasi-mesenchymal (QM) vs. non-quasi-mesenchymal (non-QM). A Random Forest machine learning algorithm was developed to predict the molecular subtype from the radiomic features. The algorithm was then applied to an independent cohort of histopathologically unclassifiable tumors with distinct clinical outcomes. The classification algorithm achieved a sensitivity, specificity and ROC-AUC (area under the receiver operating characteristic curve) of 0.84 &plusmn, 0.05, 0.92 &plusmn, 0.01 and 0.93 &plusmn, 0.01, respectively. The median overall survival for predicted QM and non-QM tumors was 16.1 and 20.9 months, respectively, log-rank-test p = 0.02, harzard ratio (HR) 1.59. The application of the algorithm to histopathologically unclassifiable tumors revealed two groups with significantly different survival (8.9 and 39.8 months, log-rank-test p &lt, 0.001, HR 4.33). The machine learning-based analysis of preoperative (CT) imaging allows the prediction of molecular PDAC subtypes highly relevant for patient survival, allowing advanced pre-operative patient stratification for precision medicine applications.

Background Bullying as a specific subtype of adverse life events is a major risk factor for poor mental health. Although many questionnaires on bullying are available, so far none covers bullying retrospectively throughout school and working life. To close this gap, the Bullying Scale for Adults (BSA) was designed. Methods Based on data of 622 participants from five European countries collected in the prospective multicenter Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, we investigated whether the BSA is a reliable and valid measurement for bullying and whether there is a difference across different diagnostic groups of early mental disorders (recent onset depressive/ psychotic patients, patients at clinical high-risk of psychosis) and healthy controls. Results Bullying experiences were significantly less frequent in healthy controls than in patient groups, with no significant differences between the three clinical groups. The BSA exhibited a high item scale discrimination (r > .3) and very good internal consistency (Cronbach's α = .93). Four factors were identified: 1. Sexual harassment, 2. Emotional Abuse, 3. Physical Abuse, 4. Problems at school. The highly significant correlation between bullying, and childhood adversities and trauma (r = .645, p Discussion The BSA is the first validated questionnaire that, in retrospective, reliably records various aspects of bullying (incl. its consequences) not only throughout childhood but also working life. It can be used to assess bullying as a transdiagnostic risk factor of mental disorders in different mental disorders, esp. psychosis and depression.

ObjectivePancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.DesignWe analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.ResultsWe observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.ConclusionSUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

Supplemental material, Online_Supplementary_File_Olle-Espluga_Karl-Franzens_Hadler_M_Economy_for_the_Common_Good_-_Covariate_balancing_MH_8_Jul_2020 for The ‘economy for the common good’, job quality and workers’ well-being in Austria and Germany by Laia Ollé-Espluga, Johanna Muckenhuber and Markus Hadler in The Economic and Labour Relations Review

The Economy for the Common Good (ECG) is an Austrian-born movement promoting an alternative economic model built on values oriented to the common welfare such as human dignity, solidarity, ecological sustainability, social justice, transparency and democratic participation. To provide (high) quality of work plays an important role in the ECG philosophy but little is known on the actual labour conditions of workers employed in such type of firms and whether they differ from those of firms in the ?regular? default economy. In this paper we focus on Austria and Germany, the countries where this economic model is most widespread, and present results on the general structure of firms following the ECG model and the working and employment conditions in these firms. We identify three main dimensions of job quality promoted by the ECG model, namely employment quality, information and worker participation, and psychosocial working conditions. Using data published in the Common Good Reports, we extracted data informing about these dimensions of job quality at an organisational level of 59 firms with at least 5 employees in Austria and Germany. We discuss which work-related features are promoted by organisations following the ECG model and compare them to the standards encouraged by the model. Results are also discussed with respect to evidence on the quality of work in the social economy.

This article aims to analyze the relationship between work-family conflict (wfc) and self-rated health in 31 countries. It argues that wfc, in line with the Sociological Stress Model (Pearlin 1987), is a major role stressor, associated with health problems of workers. The results show that wfc influences the level of self-rated health in the expected direction, when controlling for sociodemographic, family and working characteristics. Country differences exist regarding the moderating role of a country’s degree of individualism. In countries which show higher degrees of individualism, the negative health effects of wfc are stronger. The analysis uses data from the ISSP in 2012 (N=29.857) and multilevel regression models are calculated in order to analyze country differences.

Resistance to parental bone marrow (BM) grafts in F1 hybrid recipients is due to natural killer (NK) cell–mediated rejection triggered through “missing self” recognition. “Hybrid resistance” has usually been investigated in lethally irradiated F1 recipients in conjunction with pharmacological activation of NK cells. Here, we investigated BM‐directed NK‐cell alloreactivity in settings of reduced conditioning. Nonlethally irradiated (1‐3 Gy) or nonirradiated F1 (C57BL6 × BALB/c) recipient mice received titrated doses (5‐20 x 106) of unseparated parental BALB/c BM without pharmacological NK cell activation. BM successfully engrafted in all mice and multilineage donor chimerism persisted long‐term (24 weeks), even in the absence of irradiation. Chimerism was associated with the rearrangement of the NK‐cell receptor repertoire suggestive of reduced reactivity to BALB/c. Chimerism levels were lower after transplantation with parental BALB/c than with syngeneic F1 BM, indicating partial NK‐mediated rejection of parental BM. Activation of NK cells with polyinosinic–polycytidylic acid sodium salt poly(I:C), reduced parental chimerism in nonirradiated BM recipients but did not prevent hematopoietic stem cell engraftment. In contrast, equal numbers of parental lymph node cells were completely rejected. Hence, hybrid resistance leads to incomplete rejection of parental BM under reduced conditioning settings., Modifying conditioning in the hybrid resistance model reveals that lasting chimerism ensues after nonmyeloablative irradiation, even when no recipient irradiation is given, indicating that natural killer cell–mediated bone marrow rejection is incomplete in reduced conditioning settings.

1541 Sentinel-1 SAR images, acquired over Fram Strait between 2014 and 2016, were considered for sea ice drift retrieval using an open-source feature tracking algorithm. Based on this SAR image data set, 2026 and 3120 image pairs in HH and HV polarisation were used to calculate monthly mean sea ice velocities at 79 N.

AIM As adjuvant chemotherapy in colorectal cancer relies on the identification of lymph node metastases, the pathologist's dedication may have a considerable influence on postoperative survival. METHOD The aim of this retrospective study was to assess the impact of the pathologist's dedication on lymph node detection rate and postoperative survival in patients operated on by a single experienced colorectal surgeon within a 5-year period. We assessed 229 patients undergoing total mesorectal excision or complete mesocolic excision by the senior author between 1 January 2009 and 31 December 2013. Pathologists were grouped as 'general pathologist' or 'dedicated pathologist' depending on their dedication/specialization. RESULTS Dedicated pathologists found statistically significantly more lymph nodes in colorectal specimens than general pathologists [23 (interquartile range 24) vs 14 (interquartile range 11), respectively; P < 0.001]. The detection rate of ≥ 12 lymph nodes per specimen was significantly higher in the dedicated pathologist group [65/74 (87.8%) vs 105/155 (67.7%); P = 0.016]. However, postoperative survival did not differ in the respective subgroups. In the multivariable analysis by Cox proportional hazard model, International Union against Cancer Stage IV was the only factor associated with decreased disease-specific survival (hazard ratio 28.257; 95% CI 3.850-207.386; P = 0.001). CONCLUSION In our centre, the pathologist's dedication has an impact on lymph node detection rate but does not influence postoperative disease-specific survival.

Pathogenic microbes may colonize the female genital tract via sexual transmission and cause health issues like inflammation or malignancy, summarized as sexually transmitted disease (STD). A major representative of such pathogens is Trichomonas vaginalis (T.v.), whose role in the etiology of cervical cancer remains elusive. Traditional morphologic screening of cervical smears is able to detect T.v., although its identification may be complicated by look-alikes such as degenerated granulocytes and basal cells. In addition, the parasite's endosymbiont Mycoplasma hominis (M.h.) cannot be detected in the Pap test. This investigation was aimed at designing a PCR-based method to detect specific pathogenic germs by using cervical cytology slides to overcome morphologic uncertainty and increase diagnostic accuracy. To test our molecular screening method on T.v., M.h., and HPV in archival smears, we elaborated a multiplex PCR approach based on microdissection. This assay was applied to a minute quantity of starting material which harbored or was suspected to harbor T.v.; the resulting isolated DNA was used for subsequent molecular analyses of T.v., M.h., and HPV. We clarified the diagnosis of genital T.v. infection in 88 and 1.8% of morphologically suspicious and T.v.-negative cases, respectively. We also revealed a tendency of M.h. co-infection in high-risk HPV cases. In conclusion, a microdissection-based approach to detect pathogenic microbes such as T.v., HPV, and M.h. is a molecular tool easy to implement and may help to better understand the interactivity of these germs with respect to pathogenesis.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by IHC for KRT81 [quasi-mesenchymal (QM)/squamous/basal-like] and HNF1A (non-QM, overlap with exocrine/ADEX subtype). Experimental Design: We validated the different outcome of the HNF1A/KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were treated with either FOLFIRINOX (64 patients) or gemcitabine (61 patients). Results: In both cohorts with resected PDAC, the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst, and the double-negative subtype an intermediate survival (P < 0.013 and P < 0.009, respectively). In the chemotherapy cohort, the survival difference between the double-negative and the HNF1A-positive subtype was lost, whereas the dismal prognosis of KRT81-positive PDAC patients was retained (P < 0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX therapy, whereas those with HNF1A-positive tumors responded better compared with gemcitabine-based treatment (P < 0.038). Conclusions: IHC stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly different outcomes and responses to chemotherapy. These results may pave the way toward future pretherapeutic biomarker-based stratification of PDAC patients. Clin Cancer Res; 24(2); 351–9. ©2017 AACR.