Overcoming TCF4-Driven BCR Signaling in Diffuse Large B-Cell Lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of lymphoma. Despite a cure rate of 40% with standard R-CHOP therapy, patients that refract or relapse are subject to a dismal prognosis. Cases of DLBCL can be classified by their molecular expression phenotype, with the GCB-like subtype aligning with the profile of a germinal center B-cell and the ABC-like subtype aligning to that of an activated B-cell. Aggressive disease is often characterized by high levels of B-cell Receptor (BCR) signaling. This pathway engages downstream kinases responsible for stimulating proliferation and survival that play a key role under the normal circumstances of B-cell development. A comprehensive study aimed at delineating sources of inhibitor insensitivity within the BCR signaling pathway was conducted in order to identify novel drivers of disease and improve clinical outcome. A cohort of 39 aggressive lymphoma cell lines was assayed for sensitivity to Ibrutinib, a BTK inhibitor, and Umbralisib, a PI3Kδ inhibitor. Combined with intracellular phosphoflow measurements, these results revealed that higher levels of proximal BCR kinase (SYK, LYN, BTK, BLNK) and AKT (downstream of PI3K) signaling were highly linked and predictive of inhibitor insensitivity. Simultaneous inhibition of these pathways with Ibrutinib and Umbralisib consequently revealed a synergistic relationship. Following these results, a DNA copy number analysis of 673 DLBCL patient profiles was performed alongside 249 matching gene expression profiles to uncover the genomic drivers responsible for higher signaling. These results identified an enrichment of genes with transcription factor activity within regions of significant DNA copy number gain and matching transcript gain. The TCF4 transcription factor was identified within the most significant gain peak at chromosome 18q21 and led to increased transcript and protein translation. TCF4 gain was associated with the aggressive ABC-like phenotype, poor survival, and increased transcription of key BCR signaling component targets, such as BLNK, BTK, PIK3CA (PI3Kα), and the IgM heavy chain constant region. Collectively, these results identified sources of inhibitor insensitivity within DLBCL, and TCF4 was characterized as a driving force behind aggressive BCR signaling

Resonance-thrombography indices of the haemostatic process in relation to risk of incident coronary heart disease: 9 years follow-up in the Caerphilly Prospective Heart Disease Study

Global assays, such as resonance-thrombography (RTG), which measure the interaction between platelets, coagulation and fibrinolysis have been used as summary measures of risk for over two decades but have not been evaluated in epidemiological studies. We examined whether RTG indices are risk indicators for incident coronary heart disease (CHD). RTG indices, related haematological variables and other risk factors were measured between 1984 and 1988 in a cohort of 2398 British men. Reaction time (r) and amplitude of fibrin leg (AF) were associated with lifestyle risk factors. During 9 years of follow-up, 282 (12%) men developed a major new CHD event, as classified by World Health Organization criteria. On adjustment for age, only r and AF measured at baseline were related to risk of incident CHD. On multivariate adjustment in a multiple logistic regression model that included age, diastolic blood pressure, body mass index, total and high-density lipoprotein cholesterol, lifestyle risk factors and use of prescribed medicine, these associations weakened but remained significant. Additional adjustment for fibrinogen, viscosity, white cell count and fibrin D-dimer either reduced these associations to non- significance (AF) or to borderline significance(r)

Expect the unexpected: Sub-second optimization for segment routing

In this paper, we study how to perform traffic engineering at an extremely-small time scale with segment routing, addressing a critical need for modern wide area networks. Prior work has shown that segment routing enables to better engineer traffic, thanks to its ability to program detours in forwarding paths, at scale. Two main approaches have been explored for traffic engineering with segment routing, respectively based on integer linear programming and constraint programming. However, no previous work deeply investigated how quickly those approaches can react to unexpected traffic changes and failures. We highlight limitations of existing algorithms, both in terms of required execution time and amount of path changes to be applied. Thus, we propose a new approach, based on local search and focused on the quick re-arrangement of (few) forwarding paths. We describe heuristics for sub-second recomputation of segment-routing paths that comply with requirements on the maximum link load (e.g., for congestion avoidance). Our heuristics enable a prompt answer to sudden criticalities affecting network services and business agreements. Through extensive simulations, we indeed experimentally show that our proposal significantly outperforms previous algorithms in the context of time-constrained optimization, supporting radical traffic changes in few tens of milliseconds for realistic networks

Surgical treatment of aortic coarctation in adults: Beneficial effect on arterial hypertension

Background: The aim of this study was to determine the outcome after surgical repair of aortic coarctation in adults, analysing its effect on arterial blood pressure. Methods: Twenty-five adults (9 women, 16 men), mean age 43.4 years (19 to 70 years), underwent aortic coarctation surgical repair. All patients suffered from preoperative hypertension. Mean blood pressure was 182/97 mm Hg. Sixteen (64%) patients demonstrated reduced load capacity. Operative technique was resection and end-to-end anastomosis for 5 patients (20%), interposition of a Dacron-tube graft for 3 patients (12%), Dacron-patch dilatation was performed in 7 (28%) patients, and in 10 (40%) patients we performed an extra-anatomical bypass graft. Results: Early mortality occurred in 1 patient (4%). The mean blood pressure was reduced [systolic 182 mm Hg vs. 139 mm Hg (p < 0.001), diastolic 97 mm Hg vs. 83 mm Hg (p < 0.001)] in all patients. In 12 patients, blood pressure normalized immediately after surgery, in 7 patients it remained slightly elevated (systolic blood pressure between 140-160 mm Hg), and 1 patient suffered from prolonged arterial hypertension. Preoperatively, all patients were treated with antihypertensive drugs. Eleven of 20 patients received long-term medication during follow- up. In the remaining 4 patients, medication lists were unobtainable in retrospect. The mean follow-up was 7.1 years (min. 1.0 years; max. 16.6 years). One patient (5%) died from cardiac failure 12.4 years after the operation. On average, the New York Heart Association (NYHA) class was improved by 0.92. Conclusions: The surgical repair of aortic coarctation in adults can be performed with low surgical risk. Surgery reduces hypertension and permits more effective medical treatment

Naturalistic Routing Using Inverse Reinforcement Learning

This disclosure describes techniques, referred to as naturalistic routing (NR), that improve the quality of routes found by map applications by learning from users’ real-world navigation actions, accessed with user permission. The techniques leverage the principle that users, in the aggregate, tend to travel on optimal routes to reach their destinations. A machine learning model is trained using inverse reinforcement learning and provides routes that are optimal by the users’ definition of optimality, as determined from a dataset of navigation actions

Concept of an organizational model for multilateral academic cooperation : in the context of the development of a European higher education area

Having sparse experience on the international level, higher education institutions (HEI) increasingly demand solutions for the „how to do“ of successful international activities. Current discussions on subjects such as „education as commodity“, „elite-institutions versus public universities“, and „national or international focusing“ demonstrate the need for definitions and frameworks for the HE internationalization process. Expert opinion on HE development leans towards international cooperation and cross-border bundling of competencies. It is assumed that HEI will cooperate with one another internationally, each institution forming many such bonds. In the coming years either existing bilateral contracts will be enlarged to include new projects, or new partnerships will be formed. Rising cooperation of HEI on international level and the building of “excellence clusters” in HE, as requested by politics, take an initiative and situational course without plot and scientific foundation. To consolidate the necessary international collaboration at a stable level, the establishment and use of international procedures for multilateral cooperation is necessary. This aspect of current development in the HE sector is the subject of this thesis. The central question of this thesis is the following: „What are the internal and external success factors influencing multilateral academic cooperation, and how should a framework for this kind of international cooperation be designed in order to facilitate for HEI the approach to multilateral academic cooperation?“. With this orientation, the thesis addresses decision-makers in the HE sector, players in HE development, and the international public interested in HE internationalization. The practical relevance of the thesis is visible in public discussions on HE development, the ongoing Bologna Process reforming the HE sector, and in the rise of HE research as a new field of research. A focus of the thesis is put on the necessity of structural changes between partner institutions and through this, on the development of new models for management and administration of international alliances. Necessity for restructuring of financial foundation of HEI is discussed as well, in order to reach uncoupling of financial support and authority in issue directives. Thus, the developed concept ensures increased creative power and self-determination of HEI and cooperative arrangements. Organizational theory and internationalization management are well known and discussed in literature and research, and organizational models for internationalization of companies are manifold. How HEI in Germany and in European countries are organized and how they are going to change in the future is defined to a large extent. The thesis contributes the missing link between these two aspects. It proposes how the organizational model of international HE cooperation could look like, in order to best deal with competitive international markets and to efficiently cooperate with international partners. The approach of this thesis, combining the findings of organizational theories and international management was chosen for two reasons. First of all, globalization of products and markets affects the educational sector in a fundamental way. Controversial discussion about societal and economic influence of this development concerns the HEI directly and needs to be taken into account when developing their new management systems. The pressure coming from globalizing educational markets forces management of HEI to constantly think about allocation of resources, distribution of competencies, and location questions. These practical reflections require theoretical models as a back-up to provide an indication as to how to deal with this changing situation and which enable adaptation and individual planning. Secondly, the new institutional economics and other economic theories reveal indications for international management problems that were not taken into account by HE management in the past. Cross-border economic activities can be analyzed by these economic theories in a very practically oriented way and, combined with approaches on internationalization, the organization economics offer new insights and solutions to a changing educational sector. In order to handle multilateral academic cooperation in a target-oriented manner and efficiently, and thus establish successful networks, HEI have to develop legal and organizational frameworks for such cooperation. Otherwise, networking in HE will always be hindered by legal and cultural barriers and development of trustful cooperation will remain impossible. The thesis deals with this problem and, starting from the current situation of research and practice, establishes a framework for multilateral academic cooperation. One concept is presented which is suitable and adaptable for all kinds of HEI and which encompasses major aspects of multilateral academic cooperation

Kurze Besprechung eines Angriffes auf die neueren Nomenklaturbestrebungen

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