Molecular mechanisms of cell death:recommendations of the Nomenclature Committee on Cell Death 2018

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.</p

Expert Consensus on the Characteristics of Patients with Epstein–Barr Virus-Positive Post-Transplant Lymphoproliferative Disease (EBV+ PTLD) for Whom Standard-Dose Chemotherapy May be Inappropriate: A Modified Delphi Study

Introduction: Following hematopoietic stem cell transplantation or solid organ transplantation, patients are at risk of developing Epstein–Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD), which is an ultra-rare and potentially lethal hematologic malignancy. Common treatments for EBV+ PTLD include rituximab alone or combined with chemotherapy. Given specific considerations for this population, including severity of the underlying condition requiring transplant, the rigors of the transplant procedure, as well as risks to the transplanted organ, there is a group of patients with EBV+ PTLD for whom chemotherapy may be inappropriate; however, there is limited information characterizing these patients. This study aimed to reach expert consensus on the key characteristics of patients for whom chemotherapy may be inappropriate in a real-world setting. Methods: A two-round modified Delphi study was conducted to reach consensus among clinicians with expertise treating EBV+ PTLD. Articles identified in a targeted literature review guided the development of round&nbsp;1 and 2 topics and related statements. The consensus threshold for round&nbsp;1 statements was 75.0%. If consensus was achieved in round&nbsp;1, the statement was not discussed further in round&nbsp;2. The consensus thresholds for round&nbsp;2 were moderate (62.5–75.0%), strong (87.5%), or complete (100.0%). Results: The panel was composed of a total of eight clinicians (seven hematologists/hemato-oncologists) from six European countries. The panel generated a final list of 43&nbsp;consensus recommendations on the following topics: terminology used to describe patients for whom chemotherapy may be inappropriate; demographic characteristics; organ transplant characteristics; comorbidities that preclude the use of chemotherapy; EBV+ PTLD characteristics; and factors related to treatment-related mortality and morbidity. Conclusions: This modified Delphi panel successfully achieved consensus on key topics and statements that characterized patients with EBV+ PTLD for whom chemotherapy may be inappropriate. These recommendations will inform clinicians and aid in the treatment of EBV+ PTLD

Rationale and design of the Novel Uses of adaptive Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) pragmatic adaptive randomized trial: a trial protocol

Background: The prescribing of high-risk medications to older adults remains extremely common and results in potentially avoidable health consequences. Efforts to reduce prescribing have had limited success, in part because they have been sub-optimally timed, poorly designed, or not provided actionable information. Electronic health record (EHR)-based tools are commonly used but have had limited application in facilitating deprescribing in older adults. The objective is to determine whether designing EHR tools using behavioral science principles reduces inappropriate prescribing and clinical outcomes in older adults. Methods: The Novel Uses of Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) project uses a two-stage, 16-arm adaptive randomized pragmatic trial with a “pick-the-winner” design to identify the most effective of many potential EHR tools among primary care providers and their patients ≥ 65 years chronically using benzodiazepines, sedative hypnotic (“Z-drugs”), or anticholinergics in a large integrated delivery system. In stage 1, we randomized providers and their patients to usual care (n = 81 providers) or one of 15 EHR tools (n = 8 providers per arm) designed using behavioral principles including salience, choice architecture, or defaulting. After 6 months of follow-up, we will rank order the arms based upon their impact on the trial’s primary outcome (for both stages): reduction in inappropriate prescribing (via discontinuation or tapering). In stage 2, we will randomize (a) stage 1 usual care providers in a 1:1 ratio to one of the up to 5 most promising stage 1 interventions or continue usual care and (b) stage 1 providers in the unselected arms in a 1:1 ratio to one of the 5 most promising interventions or usual care. Secondary and tertiary outcomes include quantities of medication prescribed and utilized and clinically significant adverse outcomes. Discussion: Stage 1 launched in October 2020. We plan to complete stage 2 follow-up in December 2021. These results will advance understanding about how behavioral science can optimize EHR decision support to improve prescribing and health outcomes. Adaptive trials have rarely been used in implementation science, so these findings also provide insight into how trials in this field could be more efficiently conducted. Trial registration: Clinicaltrials.gov (NCT04284553, registered: February 26, 2020

Compactifications and algebraic completions of Limit groups

In this paper we consider the existence of dense embeddings of Limit groups in locally compact groups generalizing earlier work of Breuillard, Gelander, Souto and Storm [GBSS] where surface groups were considered. Our main results are proved in the context of compact groups and algebraic groups over local fields. In addition we prove a generalization of the classical Baumslag lemma which is a useful tool for generating eventually faithful sequences of homomorphisms. The last section is dedicated to correct a mistake from [BGSS] and to get rid of the even genus assumption.Comment: v2: Substantial changes to sections 7 and 8.2. Typos corrected. References added. v3: Acknowledgement correcte

Income-Related Minimum Taxation Concepts and Their Impact on Corporate Investment Decisions

In this paper we analyze the impact of various minimum taxation concepts on corporate investment decisions. These investments can be realized in the form of either a real or a financial investment. In a quantitative analysis we refer to the future values of the investments as an indicator of tax-favored and tax-discriminated projects. Varying the concept-specific loss-offset parameters and cash flow time structure and performing a Monte Carlo simulation reveals the impact of the particular minimum taxation concept. For the first time a comprehensive set of equations has been deduced to integrate different minimum tax concepts in a unique model. The resulting equations can be used as a basis for further analyses of group taxation, wealth taxation and asymmetric taxation and allows us to gain first insights into the direction and magnitude of tax distortions of possible competing concepts. Depending on the set of parameters, complex and ambiguous tax effects can be identified. The effect of minimum taxation depends on the existence and magnitude of a depreciation effect. Both effects run contrary to each other, and the depreciation effect is always greater. We find that all concepts distort in the same direction and that real investments with increasing cash flows are more likely to be discriminated by minimum taxation than financial investments or real investments with constant cash flows. However, in comparison to real investments with decreasing cash flows financial investments suffer more from income-related minimum taxation concepts. These results provide interesting information for corporate investors having to decide on the location of an investment, and for tax reform discussions

How is Democracy Applied within the EU: Combining Elements of Traditional and Innovative Democratic Practice

The EU represents a new and complex political system which, according to numerous social scholars, suffers from the so-called democratic deficit. The basic argument behind this claim is that citizens lack control of the EU because, within its political system, national parliaments of member states possess only limited powers which have not been adequately compensated through steady empowerment of the European parliament (EP). Starting from this notion, the paper will explore the application of various concepts of democracy within the political system of the EU. First and foremost, it will analyse representative democracy in the EU, which stands as a foundation of all contemporary democratic systems. However, the paper will not stop at representative democracy, but it will also look at participatory, direct and deliberative democracy as applied within the political system of the EU. These concepts of democracy can only be viewed in relation and as an addition to representative democracy, but their application is very important for the EU due to limited possibilities for developing representative democracy at the supranational level. The paper will argue that, with regard to participatory and deliberative democracy, the EU can be viewed in many respects as a showcase for the national level, because it successfully developed various mechanisms related to implementation of these concepts. Particular attention will be paid to the Lisbon Treaty, which clarified many uncertainties that previously burdened the application of democracy within the EU. It will be argued that with the Lisbon Treaty the classic argument about the EU’s democratic deficit lost some of its appeal, because this treaty transformed the EP from secondary to equal participant in the EU’s legislative process

Identification of a clinicopathologic prognostic index for newly diagnosed large B cell lymphoma patients treated with R-CHOP

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Cross-Border Group-Taxation and Loss-Offset in the EU - An Analysis for CCCTB (Common Consolidated Corporate Tax Base) and Etas (European Tax Allocation System)

The European Commission proposed to replace the currently existing Separate Accounting by an EU-wide tax system based on a Common Consolidated Corporate Tax Base (CCCTB). Besides the CCCTB, there is an alternative tax reform proposal, the European Tax Allocation System (ETAS). In a dynamic capital budgeting model we analyze the impacts of selected loss-offset limitations currently existing in the EU under both concepts on corporate crossborder real investments of MNE. The analyses show that replacing Separate Accounting by either concept can lead to increasing profitability due to cross-border loss compensation. However, if the profitability increases, the study indicates that the main criteria of decisions on location are the tax rate divergences within the EU Member States. High tax rate differentials in the Member States imply significant redistribution of tax payments under CCCTB and ETAS. The results clarify that in both reform proposals tax payment reallocations occur in favor of the holding. National loss-offset limitations and minimum taxation concepts in tendency lose their impact on the profitability under both proposals. However, we found scenarios in which national minimum taxation can encroach upon the group level, although in our model the minimum taxation's impacts seem to be slight. Moreover, we identify harmful paradoxes in ETAS due to the tax credit mechanism. Our results can contribute to the current discussion on corporate group tax harmonization within the EU and other economic zones, e.g. the US, and help to anticipate the tax effects of lossoffset restrictions under the respective tax systems

Beta-HPV 5 and 8 E6 Promote p300 Degradation by Blocking AKT/p300 Association

The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (β-HPVs); however, it is generally thought that β-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and β-HPV types. Importantly, this association appears much stronger with β-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or β-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs