Dose–response relationship between physical activity and mortality in people with non-communicable diseases: a study protocol for the systematic review and meta-analysis of cohort studies

Introduction This study protocol outlines our planned systematic review and dose-response meta-analysis of postdiagnosis physical activity and mortality in people with non-communicable diseases (NCDs). Methods and analysis This study is based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols. A systematic literature search will be conducted in various databases—namely, PubMed, Scopus and Web of Science—by two researchers in order to identify prospective observational studies that investigate postdiagnosis physical activity or activity-related energy expenditure and mortality in individuals with NCDs. The target population is adults (≥18 years of age) with one of the following nine NCDs: low back pain, type 2 diabetes mellitus, osteoarthritis, depressive disorder, chronic obstructive pulmonary disease, breast cancer, lung cancer, stroke or ischaemic heart disease. We will focus on all-cause mortality as the primary outcome and investigate indication-specific mortality as the secondary outcome. For each study identified as a result of the literature search, we will conduct graphical dose-response analyses of mortality as a function of activity-related energy consumption. If more than two studies are available for one disease, we will perform linear and non-linear dose-response meta-analyses for said disease using random-effects models. We will investigate the heterogeneity of the studies and publication bias. To assess the risk of bias and the quality of the included studies, we will use the Risk Of Bias In Non-randomised Studies - of Interventions tool, which is a Cochrane tool

Klang und Wahrnehmung – vernachlässigte Kategorien in Musiktheorie und (Historischer) Musikwissenschaft?: Podiumsdiskussion

At the beginning of this discussion, Tobias Janz introduces three areas in which musicology and music theory might benefit from a more thorough study of »sound«: (1) in music analysis, instrumental sound should not merely be understood as the manifestation of an abstract pitch-rhythm structure but the interaction of sound and structure should be acknowledged (a piano reduction from one of Haydn’s symphonies compared to one of Haydn’s piano sonatas reveals a substantially different idea about musical structure); (2) the origins of an exclusion and emancipation of the sound paradigm should be traced in music history and aesthetics, and it might be discussed to what extent a depreciation of sound has shaped our understanding of music until the present; (3) from a sociological perspective, an emphasis on sound has often been associated with popular music; since the early twentieth century, both popular and art music cultures have had a long history of treating the emancipation of sound as a predominant musical tool and medium, and thus these two »cultures« should not be regarded as entirely separate »worlds«, but rather as interactive. The other discussants broadly support the notion that sound is still a neglected area in music research by raising a variety of perspectives: our tools for describing sounds verbally and analytically are underdeveloped, and it is not always clear in which man- ner the idea of »composing [with] sounds«, for example in electronic music, should be grasped theoretically (Elena Ungeheuer); analyses of classical formal types and functions should rethink the common notion that sound and timbre are »secondary parameters« while the perception of form clearly depends on a more complex interaction between the diverse levels or parameters of the sounding events (Markus Neuwirth); established models of pitch-based analysis such as pitch-class set theory have to be complemented by aspects of register, timbre etc. which also would make their results more applicable in pedagogical situations (Lukas Haselböck); a deprecation of »Schöne Stellen« (beautiful moments) as structurally unimportant might often prevent music theorists from integrating auditory experience into analytical practice (Ludwig Holtmeier). Further aspects raised in the discussion with the audience include the idea that theory and analysis should focus more on how sounds are invented intuitively and »haptically«, for example by studying the tradition of the pianiste-compositeur and its interaction of improvisation and composition; the problem faced by a history of musical listening derived from written sources; the necessity to integrate comparisons of different performances of the same piece into a sound-based analysis of musical works; and the necessity of interdisciplinary musical research as exemplified by projects that aim to reconstruct such historical listening spaces and situations as, for instance, the Beethoven era

Assessment techniques, database design and software facilities for thermodynamics and diffusion

The purpose of this article is to give a set of recommendations to producers of assessed thermodynamic data, who may be involved in either the critical evaluation of limited chemical systems or the creation and dissemination of larger thermodynamic databases. Also, it is hoped that reviewers and editors of scientific publications in this field will find some of the information useful. Good practice in the assessment process is essential, particularly as datasets from many different sources may be combined together into a single database. With this in mind, we highlight some problems that can arise during the assessment process and we propose a quality assurance procedure. It is worth mentioning at this point, that the provision of reliable assessed thermodynamic data relies heavily on the availability of high quality experimental information. The different software packages for thermodynamics and diffusion are described here only briefly

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

SIMPLE SUMMARY: Anaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK(+) and ALK(−) ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL. ABSTRACT: In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK(+)) ALCL. Key pathogenic events in ALK-negative (ALK(−)) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK(+) and ALK(−) ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK(+) ALCL or of CD95 death-receptor signaling in ALK(−) ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity

The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL

Klang und Wahrnehmung – vernachlässigte Kategorien in Musiktheorie und (Historischer) Musikwissenschaft?: Podiumsdiskussion

At the beginning of this discussion, Tobias Janz introduces three areas in which musicology and music theory might benefit from a more thorough study of »sound«: (1) in music analysis, instrumental sound should not merely be understood as the manifestation of an abstract pitch-rhythm structure but the interaction of sound and structure should be acknowledged (a piano reduction from one of Haydn’s symphonies compared to one of Haydn’s piano sonatas reveals a substantially different idea about musical structure); (2) the origins of an exclusion and emancipation of the sound paradigm should be traced in music history and aesthetics, and it might be discussed to what extent a depreciation of sound has shaped our understanding of music until the present; (3) from a sociological perspective, an emphasis on sound has often been associated with popular music; since the early twentieth century, both popular and art music cultures have had a long history of treating the emancipation of sound as a predominant musical tool and medium, and thus these two »cultures« should not be regarded as entirely separate »worlds«, but rather as interactive. The other discussants broadly support the notion that sound is still a neglected area in music research by raising a variety of perspectives: our tools for describing sounds verbally and analytically are underdeveloped, and it is not always clear in which man- ner the idea of »composing [with] sounds«, for example in electronic music, should be grasped theoretically (Elena Ungeheuer); analyses of classical formal types and functions should rethink the common notion that sound and timbre are »secondary parameters« while the perception of form clearly depends on a more complex interaction between the diverse levels or parameters of the sounding events (Markus Neuwirth); established models of pitch-based analysis such as pitch-class set theory have to be complemented by aspects of register, timbre etc. which also would make their results more applicable in pedagogical situations (Lukas Haselböck); a deprecation of »Schöne Stellen« (beautiful moments) as structurally unimportant might often prevent music theorists from integrating auditory experience into analytical practice (Ludwig Holtmeier). Further aspects raised in the discussion with the audience include the idea that theory and analysis should focus more on how sounds are invented intuitively and »haptically«, for example by studying the tradition of the pianiste-compositeur and its interaction of improvisation and composition; the problem faced by a history of musical listening derived from written sources; the necessity to integrate comparisons of different performances of the same piece into a sound-based analysis of musical works; and the necessity of interdisciplinary musical research as exemplified by projects that aim to reconstruct such historical listening spaces and situations as, for instance, the Beethoven era

Klang und Wahrnehmung – vernachlässigte Kategorien in Musiktheorie und (Historischer) Musikwissenschaft?: Podiumsdiskussion

At the beginning of this discussion, Tobias Janz introduces three areas in which musicology and music theory might benefit from a more thorough study of »sound«: (1) in music analysis, instrumental sound should not merely be understood as the manifestation of an abstract pitch-rhythm structure but the interaction of sound and structure should be acknowledged (a piano reduction from one of Haydn’s symphonies compared to one of Haydn’s piano sonatas reveals a substantially different idea about musical structure); (2) the origins of an exclusion and emancipation of the sound paradigm should be traced in music history and aesthetics, and it might be discussed to what extent a depreciation of sound has shaped our understanding of music until the present; (3) from a sociological perspective, an emphasis on sound has often been associated with popular music; since the early twentieth century, both popular and art music cultures have had a long history of treating the emancipation of sound as a predominant musical tool and medium, and thus these two »cultures« should not be regarded as entirely separate »worlds«, but rather as interactive. The other discussants broadly support the notion that sound is still a neglected area in music research by raising a variety of perspectives: our tools for describing sounds verbally and analytically are underdeveloped, and it is not always clear in which man- ner the idea of »composing [with] sounds«, for example in electronic music, should be grasped theoretically (Elena Ungeheuer); analyses of classical formal types and functions should rethink the common notion that sound and timbre are »secondary parameters« while the perception of form clearly depends on a more complex interaction between the diverse levels or parameters of the sounding events (Markus Neuwirth); established models of pitch-based analysis such as pitch-class set theory have to be complemented by aspects of register, timbre etc. which also would make their results more applicable in pedagogical situations (Lukas Haselböck); a deprecation of »Schöne Stellen« (beautiful moments) as structurally unimportant might often prevent music theorists from integrating auditory experience into analytical practice (Ludwig Holtmeier). Further aspects raised in the discussion with the audience include the idea that theory and analysis should focus more on how sounds are invented intuitively and »haptically«, for example by studying the tradition of the pianiste-compositeur and its interaction of improvisation and composition; the problem faced by a history of musical listening derived from written sources; the necessity to integrate comparisons of different performances of the same piece into a sound-based analysis of musical works; and the necessity of interdisciplinary musical research as exemplified by projects that aim to reconstruct such historical listening spaces and situations as, for instance, the Beethoven era

Spectrum-Wide Exploration of Human Adenoviruses for Breast Cancer Therapy

Oncolytic adenoviruses (Ads) are promising tools for cancer therapeutics. However, most Ad-based therapies utilize Ad type 5 (Ad5), which displays unsatisfying efficiency in clinical trials, partly due to the low expression levels of its primary coxsackievirus and adenovirus receptor (CAR) on tumor cells. Since the efficacy of virotherapy strongly relies on efficient transduction of targeted tumor cells, initial screening of a broad range of viral agents to identify the most effective vehicles is essential. Using a novel Ad library consisting of numerous human Ads representing known Ad species, we evaluated the transduction efficiencies in four breast cancer (BC) cell lines. For each cell line over 20 Ad types were screened in a high-throughput manner based on reporter assays. Ad types featuring high transduction efficiencies were further investigated with respect to the percentage of transgene-positive cells and efficiencies of cellular entry in individual cell lines. Additionally, oncolytic assay was performed to test tumor cell lysis efficacy of selected Ad types. We found that all analyzed BC cell lines show low expression levels of CAR, while alternative receptors such as CD46, DSG-2, and integrins were also detected. We identified Ad3, Ad35, Ad37, and Ad52 as potential candidates for BC virotherapy