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High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.

Das klassische Hodgkin-Lymphom (cHL) ist auf histologischer Ebene gekennzeichnet durch ein quantitativ dominierendes Begleitinfiltrat, das in Abhangigkeit vom histologischen Subtyp und EBV(Epstein-Barr-Virus)-Status eine unterschiedliche Zusammensetzung aufweist. Derzeitig gultige pathogenetische Konzepte postulieren, dass die malignen Zellen in Form der sogenannten Hodgkin- bzw. Reed-Sternberg(HRS)-Zellen eine dominante Rolle in der Rekrutierung verschiedener Immunzellen einnehmen, die wiederum zum Uberleben der Tumorzellpopulation beitragen. Unterstutzt wird diese Hypothese durch genetische Analysen, die entscheidend dazu beigetragen haben, relevante Mechanismen zu identifizieren, mithilfe derer sich die HRS-Zellen einer wirksamen Immunantwort entziehen konnen. Neben einer reduzierten bzw. defekten Antigenprasentation bedingt durch strukturelle Chromosomenaberrationen und Mutationen in Komponenten bzw. Regulatoren der Haupthistokompatibilitatskomponenten Klasse I und II, kommen vor allem Kopienzahlzugewinne des 9p24.1-Lokus eine bedeutsame Rolle zu. Letztere resultieren zumeist in einer verstarkten Expression von Liganden des programmierten Zelltod-Proteins PD‑1, die durch die Interaktion mit diesem auf T‑Lymphozyten exprimierten Rezeptor zu einer Suppression der Immunantwort fuhren. Die Reversibilitat dieser inhibitorischen Rezeptor-Liganden-Wechselwirkung wird klinisch in Form sog. Checkpoint-Inhibitoren genutzt, die bei Patienten mit cHL, insbesondere auch in der Rezidivsituation, mit im Vergleich zu vielen anderen Tumorentitaten imposanten Ansprechraten uberzeugt haben. Ultimatives Ziel ist die Integration dieser Informationen in prognostische bzw. pradiktive Modelle, die eine rationale Risikostratifizierung und basierend darauf eine Selektion optimaler Therapieregime ermoglicht.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children’s Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease.

Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.

In the last few years, the collaboration of services between the service-oriented, cross-enterprise vehicle application frameworks has gradually increased to generate novel and more complicated vehicle services for the automotive industry. In these service collaboration scenarios, where heterogeneous application frameworks participate to realize complex vehicle services, a source of discord that emerges is that the service providers must always check, before the service deployment, whether the clients or service consumers on the other side of the communication link are compatible with a given service’s API (Application Program Interface). While using standardized templates like ontologies for API’s semantic specifications are crucial for a service discovery and semantic interoperability, nevertheless, accessing these service APIs’ semantic data using a standardized and understandable syntactical specification template is also equally substantial to ease services interoperability. In fact, such complex service collaboration scenarios motivate this research work which proposes a design approach towards standardized, domain specific, platform-agnostic semantic and syntactic specification of vehicle services API models. This paper also uses a typical vehicle domain case study to illustrate the design approach and a reference mapping between the platform-agnostic semantics specifications of a vehicle service API ontological model and its corresponding language-neutral, syntactic representation using the OpenAPI standard.

Semantic alignment of application software components’ ontologies represents a great interest in vehicle application domains that manipulate heterogeneous overlapping knowledge application frameworks. In the past few years, with the growth in the novel vehicle service requirements such as autonomous driving, V2X (Vehicle-to-Vehicle communication) and many others, automotive application software component models are becoming increasingly collaborative with other qualified cross-enterprise industrial partners to accomplish these complex service requirements. The most daunting impediment to this cross-enterprise collaboration is semantic interoperability. For efficient services collaboration through cross-enterprise semantic interoperability between the vehicle application frameworks’ software components, aligning the interface ontologies of these components by identifying the depth of semantic alignment relationships between the concepts of the interface ontologies is the major focus of this paper. In contrast to several existing ontology structural metrics, this work defines, evaluates and validates ontology metrics to measure the depth of semantic alignment between the vehicle domain software component frameworks’ interface ontological models. To emphasize the substantial role of semantic alignment of software component frameworks’ interface ontologies in semantic interoperability, a typical vehicle domain case study involving vehicle applications is considered for demonstration.

In the beginning of every security analysis or penetration test of a system, information about the target has to be gathered. On IT-Systems a port scan is usually performed as a first step of an investigation. Since the communication protocols differ in automotive systems, generic port scanning tools can’t be used for a security analysis of CANs. More complex protocols have a higher likelihood of implementation errors and bugs. On CAN networks, such payloads are transferred through International Standard Transport Protocol (ISO-TP) communication. We designed a new methodology to identify ISO-TP endpoints in automotive networks. Every of these endpoints can provide exploitable application layer protocols and therefor has to be considered during penetration testing and security analysis. We contribute a new scan approach for the automated evaluation of possible attack surfaces in automotive CAN networks which has a higher coverage and multiple advantages than state of the art approaches.

We briefly describe a tutorial on the application of Eye-Tracking technology for Software Engineering Education. We will showcase our setup of a large-scale Eye-Tracking-Classroom and its usage for real-time improvement of traditional learning scenarios in Software Engineering Education. We will focus on the integration of gaze data into modern integrated development environments (IDEs) and demonstrate a complete workflow for its usage in co-located multi-user Eye-Tracking-Environments.

Software process models are important in software projects in order to give the work of a project guidelines or a framework. However, teaching process models in higher education seems to be quite challenging. This has to do with the fact that undergraduates have no experience with projects in which process models are used. The theoretical mediation of process models is initially on a very abstract level. For this reason, we chose to combine two didactic approaches, namely problem-based learning and project work. Various traditional plan-driven process models have been expanded in courses in Software Engineering with agile process models. The Scrum Framework is the focus of consideration of this paper. Three Universities of Applied Sciences which cooperate in the EVELIN project focused on Scrum as a process model and integrated it into their teaching. Since the respective concepts of implementation differ, they should be presented and compared in this article to presents some practice approaches. The goal of this presentation of is a uniform evaluation in order to obtain insights from different perspectives. This comparison can draw conclusions for possible necessary improvements of the respective concepts.

Code reviews are an essential part of quality assurance in modern software projects. But despite their great importance, they are still carried out in a way that relies on human skills and decisions. During the last decade, there have been several publications on code reviews using eye tracking as a method, but only a few studies have focused on the performance differences between experts and novices. To get a deeper understanding of these differences, the following experiment was developed: This study surveys expertise-related differences in experts’, advanced programmers’, and novices’ eye movements during the review of eight short C++ code examples, including correct and erroneous codes. A sample of 35 participants (21 novices, 14 advanced and expert programmers) were recruited. A Tobii Spectrum 600 was used for the data collection. Measures included participants’ eye movements during the code review, demographic background data, and cued retrospective verbal comments on replays of their own eye movement recordings. Preliminary results give proof for experience-related differences between participants. Advanced and expert programmers performed significantly better in case of error detection and the eye tracking data implies a more efficient reviewing strategy.

Follicular lymphoma (FL) is a common indolent lymphoma in which clinical and biological heterogeneity is increasingly recognized.[1][1] Although median survival for newly diagnosed FL patients may be as high as 18 years,[2][2] a significant subset of patients is at risk of adverse outcomes. In

In the age of the Internet of Things, it is becoming increasingly important to integrate knowledge about the development of secure systems (Secure Software Engineering) into academic teaching. However, teaching IT Security and Secure Software Engineering to non-computer scientists is rare. Therefore, we focus our research on the integration of IT Security into software engineering education of non-computer scientists, particularly electrical engineers, by means of inductive teaching- and learning-arrangements. After collecting students’ preconceptions of IT Security and Secure Software Engineering in prior work, this paper now contributes with a first mapping of these preconceptions with corresponding learning content as well as suitable inductive teaching methods to be able to create new lecture and exercise units and improve academic learning and teaching in both areas.

Experts predict that more IT-Security specialists will be needed in the coming years, but in current higher education in engineering disciplines, this topic is hardly addressed. Newer learning methods such as game-based learning (GBL) are enjoying an increasing popularity as their improvement in the education of subject specific topics can be proven by a variety of studies. We chose Educational Escape Rooms (EduER) as a GBL-tool to impart IT-Security in higher education of engineers. In our Escape Room (ER), the students try to solve puzzles and riddles with learned knowledge on the emphasis of cryptography. This paper first deals with a brief introduction to GBL and EduERs, followed by the design of our ER concept, containing different tasks with focus on the topic of cryptography. The tasks cover different cryptographic methods and hash algorithms, e.g. AES, RSA, SHA3. Afterwards the experimental study is presented. The study of the EduER was carried out with students from the bachelor’s program in Electrical Engineering and Information Technology at the OTH Regensburg. The participants were divided into three groups of 5 to 8 persons each. They received a briefing with important information, followed by the ER execution, a debriefing afterwards and an exam-like evaluation sheet to test their learned knowledge. Finally, first basic results are presented.

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki-67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression-based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki-67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk-adapted prospective clinical trials in the future.

AIM Recently, [F]tetrafluoroborate ([F]TFB) has been introduced as a versatile PET probe for imaging the human sodium/iodide symporter activity. This pilot study aimed to compare [F]TFB-PET/CT with [I]NaI-PET/CT imaging in thyroid cancer patients. METHODS Nine patients with newly diagnosed differentiated thyroid cancer underwent both [F]TFB- and [I]NaI-PET/CT after total thyroidectomy. PET/CT scans were visually analyzed for the presence of remnant thyroid tissue and for metastatic lesions on a patient and lesion basis. For semiquantitative analysis, thyroid remnant/tumor to blood pool ratios were calculated. RESULTS All patients presented with positive [F]TFB and [I]NaI-PET/CT scans. Retention of I in remnant thyroid tissue was significantly higher as compared with [F]TFB (P < 0.01). In a lesion-based analysis, both tracers identified an almost equal number of foci with [F]TFB depicting a total of 41 foci and I a total of 40 foci, respectively. In 6 of 9 patients, both radiopharmaceuticals returned an identical number of foci. Two I-positive benign thyroid remnants were missed by [F]TFB-PET/CT in a single patient. In another case, both tracers identified different thyroid remnant tissues in the cervical region. Notably, [F]TFB demonstrated additional (I-negative) cervical lymph node metastases in 2 patients, leading to an overall agreement between the radiotracers of 91% (74/81 foci). DISCUSSION In this pilot study, [F]TFB-PET was not inferior to [I]NaI-PET for detecting thyroid cancer and its metastases and was able to detect [I]NaI-PET-negative viable differentiated thyroid cancer metastases. Further clinical evaluation as a PET tracer for imaging thyroid pathophysiology and human sodium/iodide symporter expressing neoplasms is highly warranted.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies with approximately one-third of cases designated as PTCL-not otherwise specified (PTCL-NOS). Using gene expression profiling (GEP), we have previously defined two major molecular subtypes of PTCL-NOS; PTCL-GATA3 and PTCL-TBX21 that have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the two subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the two subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (p=0.03). The IHC algorithm classification showed high inter-observer reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n=124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (p=0.003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (p= 0.0015). Additionally, the two IHC-defined subtypes were significantly associated with distinct morphological features (p

Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression–based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography–guided response assessment and the evolving cHL treatment landscape.

Background Patients with mantle cell lymphoma (MCL) follow a heterogeneous clinical course. While they generally require treatment initiation shortly after diagnosis, it is unclear whether deferring treatment in selected patients with an indolent clinical behavior affects their overall outcome. Patients and methods In this population-based study, all patients diagnosed with MCL during 1998–2014 were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. The associations between clinico-pathologic characteristics, including the expression of Ki67, SOX11, and TP53, and time to treatment (TtT) and OS were analyzed. Results A total of 440 patients with MCL were evaluated: 365 (83%) received early treatment and 75 (17%) were observed ≥3 months. In the observation group, 54 (72%) patients had a nodal presentation, 16 (21%) a non-nodal presentation, and 5 (7%) had only gastrointestinal involvement. Characteristics associated with deferred treatment included good performance status, no B symptoms, low LDH, non-bulky disease, non-blastoid morphology, and lower Ki67 values. The median TtT in the observation group was 35 months (range 5–79), and 60 (80%) patients were observed beyond 12 months. The median OS was significantly longer in the observation group than in the early treatment group (72 versus 52.5 months, respectively,P = 0.041). In multivariable analysis, treatment decision was not associated with OS [HR 0.804 (95% CI 0.529–1.221),P = 0.306]. Conclusions A subgroup of patients with MCL may be safely observed from diagnosis without negatively impacting their outcomes, including patients with non-nodal presentation as well as asymptomatic patients with low burden nodal presentation and a low proliferative rate.

The number of IoT devices in SCADA and ICS systems is rising quickly, especially in the domain of critical infrastructures. But these kinds of systems are performing mission critical tasks like controlling devices in industrial facilities or substations in the smart grid. Therefore, they are subject to a lot of regulatory standards. Yet, to provide remote access over the internet, special architectures are developed to integrate a network interface into these devices without inferring with the actual functionality. However, these architectures either lack security measures against cyber-attacks or do not offer the necessary performance for time-critical communication interfaces. To solve that, an architecture consisting of three units is introduced in this paper to provide a network interface with extensive security measures and a high performance. The main feature is the isolation of the cryptographic functionality onto an additional MCU. After proposing the basic concept, the paper presents many implementation details. Based on the current state of implementation, a concept validation of the realized architecture is described.

With the rising complexity and processing power of modern computer systems, the amount of MCU on a single PCB also rises. These microcontrollers often need to communicate with each other to exchange payload and control information in a bidirectional manner. Today’s well-established communication protocols in MCUs either do not fit modern transmission speed requirements or do have an inappropriate master-slave attribute, which does not allow the communication partners to have equal bus access rights. Therefore, this paper introduces an extension of the Serial Peripheral Interface (SPI) to allow an equally distributed access right for the communication interface between two microcontrollers. It simultaneously does fit modern transmission speed requirements of a common network interface, so that the message transmission does not constitute a bottleneck in data processing. Besides the protocol design, we do also provide a first prototype implementation, which constitutes a proof of concept.

Modern compute architectures often consist of multiple CPU cores to achieve their performance, as physical properties put a limit on the execution speed of a single processor. This trend is also visible in the embedded and real-time domain, where programmers are forced to parallelize their software to keep deadlines. Additionally, embedded systems rely increasingly on modular applications, that can easily be adapted to different system loads and hardware configurations.

UML (Unified Modeling Language) is the current de facto as well as de jure standard (ISO/IEC 19505:2012) notation to visualize models in software development. UML provides essential guidelines and rules to visualize and understand complex software systems. This is the reason why it has become part of curricula for software engineering courses at many universities worldwide. It is well known, however, that UML is hard to grasp for novices, mainly due to its complexity. In order to tackle the problem of teaching UML to novice students appropriately, it is inevitable to understand their needs and problems much better than we do now. This paper presents empirical insights into students��� problems when developing common UML diagrams. Identified problems are generalized, giving rise to a problem catalogue that is derived from our empirical findings, thus establishing a basis for addressing these problems through focused learning arrangements.

The National Institute of Standards and Technology (NIST) started the standardization process for lightweight cryptography algorithms in 2018. By the end of the first round, 32 submissions have been selected as 2nd round candidates. NIST allowed designers of 2nd round submissions to provide small updates on both their specifications and implementation packages. In this work, we introduce a benchmarking framework for evaluating the performance of NIST Lightweight Cryptography (LWC) candidates on embedded platforms. We show the features and application of the framework and explain its design rationale. Moreover, we provide information on how we aim to present up-to-date performance figures throughout the NIST LWC competition. In this paper, we present an excerpt of our software benchmarking results regarding speed and memory requirements of selected ciphers. All up-to-date results, including benchmarking different test cases for multiple variants of each 2nd round algorithm on five different microcontrollers, are periodically published to a public website. While initially only the reference implementations were available, the ability of automatically testing the performance of the candidate algorithms on multiple platforms becomes especially relevant as more optimized implementations are developed. Finally, we show how the framework can be extended in different directions: support for more target platforms can be easily added, different kinds of algorithms can be tested, and other test metrics can be acquired. The focus of this paper should rather lay on the framework design and testing methodology than on the current results, especially for reference code.

The automotive industry is eventually evolving into a complex network of services. The heterogeneous and distributed nature of automotive software systems demands flexible software components which can operate in different environments. Because of heterogeneous automotive development environments, the domain experts, must cope with too many diversities, adaption layers, and incompatibilities to design applications for the current generation of autonomous driving vehicles. In this context, interface adaptation is a promising approach to achieve flexibility without directly changing the respective components. AUTOSAR, which is the de-facto standard for describing automotive system architecture and is a hugely comprehensive standard allowing designers full control from abstract system description to bare metal level deployment. However, the vehicle subsystems have still evolved to include multifarious high-level domains not covered by AUTOSAR e.g. Infotainment, Telematics etc. Therefore, it seems beneficial to bridge the semantic gaps between AUTOSAR applications and other standards of automotive application domains. The goal of this paper is to investigate interface semantic mapping and achieve transparent integration of domain-specific applications using the translation of semantics among the AUTOSAR platform software component models and other software components models of open source development platforms e.g. GENIVI. A key goal of such a modelling approach is the reuse of existing interface description languages and respective code generators. This will enhance future interoperability and decrease in incompatibility among these platforms.

Introduction The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts. Patients and Methods The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310). Results Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell–like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry). Conclusion Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma with distinct clinicopathologic features. It is typified by the presence of lymphocyte predominant (LP) cells, which are CD20(+) but CD15(-) and CD30(-) and are found scattered amongst small B lymphocytes arranged in a nodular pattern. Despite frequent and often late or multiple relapses, the prognosis of NLPHL is very favorable. There is an inherent risk of secondary aggressive non-Hodgkin lymphoma (NHL) and studies support that risk is highest in those with splenic involvement at presentation. Given disease rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma (CHL). This review provides an overview of the existing literature describing pathological subtypes, outcome and treatment approaches for NLPHL.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first���line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse., publishedVersion

Although there has been much speculation about the potential of Augmented Reality (AR) in teaching for learning material, there is a significant lack of empirical proof about its effectiveness and implementation in higher education. We describe a software to integrate AR using the Microsoft Hololens into UML (Unified Modeling Language) teaching. Its user interface is laid out to overcome problems of existing software. We discuss the design of the tool and report a first evaluation study. The study is based upon effectiveness as a metric for students performance and components of motivation. The study was designed as control group experiment with two groups. The experimental group had to solve tasks with the help of the AR modeling tool and the control group used a classic PC software. We identified tendencies that participants of the experimental group showed more motivation than the control group. Both groups performed equally well.

Scalable Software Support for Dependable Embedded Systems (S\(^{3}\)DES) achieves fault tolerance by utilizing spatial software-based triple modular redundancy for computational and voter processes on application level. Due to the parallel execution of the replicas on distinct CPU cores it makes a step towards software-based fault tolerance against transient and permanent random hardware errors. Additionally, the compliance with real-time requirements in terms of response time is enhanced compared to similar approaches. The replicated voters, the introduced mutual voter monitoring and the optimized arithmetic encoding allow the detection and compensation of voter failures without the utilization of backward recovery. Fault injection experiments on real hardware reveal that S\(^{3}\)DES can detect and mask all injected data and program flow errors under a single fault assumption, whereas an uncoded voting scheme yields approx. 12% silent data corruptions in a similar experiment.

Sharing data across multiple tasks in multiprocessor systems has intensively been studied in the past decades. Various synchronization protocols, the most well-known being the Priority Inheritance Protocol or the Priority Ceiling Protocol, have been established and analyzed so that blocking times of tasks waiting to access a shared resource can be upper bounded. To the best of our knowledge, all of these protocols share one commonality: Tasks that want to enter a critical section, that is already being executed by another task, immediately get blocked. In this paper, we introduce the Asynchronous Priority Ceiling Protocol (A-PCP), which makes use of aperiodic servers to execute the critical sections asynchronously, while the calling task can continue its work on non-critical section code. For this protocol, we provide a worst-case response time analysis of the asynchronous computations, as well as necessary and sufficient conditions for a feasibility analysis of a set of periodic tasks using the proposed synchronization model on a system that preemptively schedules the tasks under the rate-monotonic priority assignment.

As the world is getting more connected, the demands of services in automotive industry are increasing with the requirements such as IoT (Internet of Things) in cars, automated driving, etc. Eventually, the automotive industry has evolved to a complex network of services, where each organization depends on the other organizations, to satisfy its service requirements in different phases of the vehicle life cycle. Because of these heterogeneous and complex development environments, most of the vehicle component interface models need to be specified in various manifestations to satisfy the semantic and syntactic requirements, specific to different application development environments or frameworks. This paper describes an approach to semantic analysis of components interfaces description models of heterogeneous frameworks, that are used for vehicle applications. The proposed approach intends to ensure that interface description models of different service-based vehicle frameworks can be compared, correlated and re-used based on semantic synergies, across different vehicle platforms, development environments and organizations. The approach to semantic synergy exploration could further provide the knowledge base for the increase in interoperability, overall efficiency and development of an automotive domain specific general software solutions, by facilitating coexistence of components of heterogeneous frameworks in the same high-performance ECU for future vehicle software.

Purpose High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. Patients and Methods We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. Results We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non–light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive–transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. Conclusion We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression–based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx’s utility for routine diagnostic purposes and therapeutic decision making.

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) is a newly defined entity in the latest World Health Organization Classification. Accurate diagnosis would appear to mandate fluorescence in situ hybridization (FISH) for all tumors with diffuse large B-cell lymphoma (DLBCL) morphology. We present the results of FISH, cell-of-origin, and immunohistochemistry (IHC) testing from 1228 DLBCL biopsies from 3 clinical trials and a population-based registry. HGBL-DH/TH made up 7.9% of the DLBCL, confined primarily to the germinal center B-cell-like (GCB; 13.3%) compared with activated B-cell-like (ABC; 1.7%) subtype (P < .001). HGBL-DH/TH with BCL2 rearrangement is a GCB phenomenon with no cases observed in 415 ABC DLBCL. A screening strategy restricting FISH testing to tumors of GCB subtype (by Lymph2Cx or Hans IHC) plus dual protein expression of MYC and BCL2 by IHC could limit testing to 11% to 14% of tumors, with a positive predictive value of 30% to 37%; however, this strategy would miss approximately one-quarter of tumors with HBGL-DH/TH with BCL2 rearrangement and one-third of all HGBL-DH/TH. These results provide accurate estimation of the proportion of HGBL-DH/TH among tumors with DLBCL morphology and allow determination of the impact of various methods available to screen DLBCL tumors for FISH testing.

Writing, with no doubt, is besides reading a core competency which allows us to "exploit" knowledge in general. It also makes possible the exploration of software engineering's core issues. Especially within this context it is necessary to master the reading of complex texts as well as to be able to write in an appropriate academic expression. With regard to studies in software engineering this seems to be obvious, but in fact the opposite is the reality. Therefore measures to improve these skills seemed to be necessarily applied. At the Ostbayerische Technische Hochschule (OTH, University of Applied Sciences, Regensburg) a new format, the so called c∗lab, was installed during the winter semester 2017. This was a course which followed the principle of "Writing Across the Curriculum" (WAC). Organized parallel to a lecture of learning how to program the language C, and addressing students of the first semester, the course was a complete voluntary offer in addition to the general standard courses and lectures of the faculty. Students who participated not only reflected on C and its principles, nor only on writing as a self purpose, but they also learned to express technical thoughts and ideas by the use of didactic methods. The idea to transfer also basic LTeX concepts to write a paper based on the IEEE bare_conf.tex-template were also planned. The course followed the idea of student's-centred learning. This paper presents the main structure, goals, and means of the c∗lab, and the theory behind. It also embeds the course within the horizon of experiences of teaching writing skills at the Laboratory for Safe and Secure Systems (LaS3) at the faculty of electronic and information engineering at the OTH Regensburg. First experiences have shown that participants increase writing skills and their idea of the importance of writing.

In logical circuits, like arithmetic operations in a processor system, arbitrary faults become a more tremendous aspect in future. Modern manufacturing processes lead to less reliability and higher vulnerability of software execution to soft-errors. The correctness of certain results is important especially for safety-critical applications whose reliability depends on the fault-free execution of each single instruction and the dependencies between them. The more complex a software is the more unreliable the outcome is. But, there is a contrary effect. If the probability for multiple faults increases, there is also the chance that two faults compensate each other and the result is correct again. This paper presents the basic ideas for such a reliability evaluation of a software's data flow with arbitrary soft-errors and the effect of fault compensation. Further, this evaluation provides a possibility to compare different implementations of a data flow with respect to the reliability. This is shown by the comparison of two different error codes as alternatives for coded data processing.

Adoptive transfer of donor-derived cytolytic T-lymphocytes (CTL) has evolved as a promising strategy to improve graft-versus-leukemia (GvL) effects in allogeneic hematopoietic stem-cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)-reactive CD8(+) CTL with central and effector memory phenotype in a new allogeneic donor-patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA(+) donor CD8(+) T cells with either single HLA antigen-mismatched or HLA-matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine-optimized short to intermediate (i.e., 2-8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg(null) mice when engraftment with patient AML reached bone marrow infiltration of 1-5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA-mismatched and strong reduction of HLA-matched AML infiltration, respectively. Most importantly, mice receiving AML-reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML-reactivity ex vivo. Moreover, injections with human IL-15 clearly promoted CTL persistence. In summary, we show that naive donor-derived CD8(+) CTL effectively combat patient AML blasts in immunodeficient mice. The donor-patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML-reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T-cell receptors for redirecting immunity to leukemias even in a patient-individualized manner.

Graft versus host disease (GvHD) is a clinically important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its diagnosis relies on clinical and histopathological findings. In order to evaluate and improve inter-institutional diagnostic agreement on histological diagnosis and grading of acute gastrointestinal GvHD, we conducted a round robin test, which included 33 biopsies from 23 patients after HSCT. Five pathologists from different institutions independently evaluated the original sections from the biopsies submitted for diagnosis. Based on their results, consensus qualitative criteria for the assessment of typical histological features of GvHD (e.g., apoptosis, crypt destruction, mucosa denudation) were proposed, including detailed descriptions as well as histological images. In a second round robin test with involvement of the same pathologists, the reproducibility of both diagnosis and grading had improved. Remaining differences were mostly related to differential diagnostic considerations, including viral infection or toxic side effects of medication, which should be resolved by integrating histopathological findings with proper clinical information.

This paper aims to provide an overview of the interdisciplinary combination of educational science, psychology, software engineering and the eye tracking methodology. The domain of software engineering is offering great potential for applied eye tracking research and in turn it can benefit from the possibilities of this upcoming technology as well. Nevertheless, software engineering has to struggle with some obstacles. These are namely the different terms, missing guidelines for experimental setups and a lack of common and standardized metrics. If eye tracking should be used in a broader way these problems must be solved. The main purpose of this paper is to list all eye tracking metrics which are relevant for software engineering and to give guidelines to help beginners by avoiding possible pitfalls.