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"Paschen, Michael"
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Mitarbeiterbeurteilungssysteme – Wie sie wirklich funktionieren
In diesem Beitrag werden die wichtigsten Rahmenbedingungen, Spielregeln und Argumentationshilfen zusammengefasst, die dem Erfolg, der Akzeptanz und der konsequenten Anwendung eines Mitarbeiterbeurteilungssystems zugrunde liegen.
Journal Article
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8
+
T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often
JAK1
or
JAK2,
protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic
JAK1/2
losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.
IFNγ secretion by CD8
+
T cells is critical for immunotherapy efficacy. In this study, the authors show that melanoma patients can become resistant to immunotherapy by acquiring chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2.
Journal Article
Direct measurement of individual phonon lifetimes in the clathrate compound Ba7.81Ge40.67Au5.33
Engineering lattice thermal conductivity requires to control the heat carried by atomic vibration waves, the phonons. The key parameter for quantifying it is the phonon lifetime, limiting the travelling distance, whose determination is however at the limits of instrumental capabilities. Here, we show the achievement of a direct quantitative measurement of phonon lifetimes in a single crystal of the clathrate Ba
7.81
Ge
40.67
Au
5.33
, renowned for its puzzling ‘glass-like’ thermal conductivity. Surprisingly, thermal transport is dominated by acoustic phonons with long lifetimes, travelling over distances of 10 to 100 nm as their wave-vector goes from 0.3 to 0.1 Å
−1
. Considering only low-energy acoustic phonons, and their observed lifetime, leads to a calculated thermal conductivity very close to the experimental one. Our results challenge the current picture of thermal transport in clathrates, underlining the inability of state-of-the-art simulations to reproduce the experimental data, thus representing a crucial experimental input for theoretical developments.
Phonon lifetime is a fundamental parameter of thermal transport however its determination is challenging. Using inelastic neutron scattering and the neutron resonant spin-echo technique, Lory et al. determine the acoustic phonon lifetime in a single crystal of clathrate Ba7.81Ge40.67Au5.33.
Journal Article
Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation
NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.
Overabundance of apolipoprotein C3 (ApoC3) is associated with atherosclerosis. Speer and colleagues demonstrate that ApoC3 activates the NLRP3 inflammasome via a non-canonical pathway contributing to inflammation and development of atherosclerosis.
Journal Article
The Contribution of Complementary and Alternative Medicine to Reduce Antibiotic Use: A Narrative Review of Health Concepts, Prevention, and Treatment Strategies
Aim. The aim of this narrative review was to explore the potential contributions of CAM to reduce antibiotic use. Methods. We searched PubMed, Embase, and Cochrane Database of Systematic Reviews with a specific, limited set of search terms and collected input from a group of expert CAM researchers to answer the question: What is known about the contribution of CAM health and health promotion concepts, infection prevention, and infection treatment strategies to reduce antibiotic use? Results. The worldview-related CAM health concepts enable health promotion oriented infection prevention and treatment aimed at strengthening or supporting the self-regulating ability of the human organism to cope with diseases. There is some evidence that the CAM concepts of health (promotion) are in agreement with current conceptualization of health and that doctors who practice both CAM and conventional medicine prescribe less antibiotics, although selection bias of the presented studies cannot be ruled out. There is some evidence that prevention and some treatment strategies are effective and safe. Many CAM treatment strategies are promising but overall lack high quality evidence. Conclusions. CAM prevention and treatment strategies may contribute to reducing antibiotic use, but more rigorous research is necessary to provide high quality evidence of (cost-)effectiveness.
Journal Article
Differences in bioimpedance-derived fluid status between two versions of the Body Composition Monitor
•We investigated different versions of the Body Composition Monitor (BCM).•The version 3.2.5 BCM measured on average >0.5 L more overhydration than the version 3.3.3 BCM.•Differences between BCM versions are most evident in the high-frequency range.•Clinicians are advised to only use BCM devices of the same version.
The Body Composition Monitor (BCM) (Fresenius Medical Care) measures body impedances in alternating currents to subsequently calculate fat and lean tissue mass, fluid compartments, and overhydration (OH). The aim of this study was to investigate differences between two versions of the BCM (an older version, 3.2.5, and a newer version, 3.3.3).
Between September 2021 and December 2021, 28 hemodialysis patients were included to undergo BCM measurements before each of 14 consecutive dialysis sessions with versions 3.2.5 and 3.3.3 devices. Measurements were performed according to instructions provided by the manufacturer. Differences between BCM devices were tested for statistical significance using paired Wilcoxon tests, neglecting clustering.
A total of 288 measurement pairs of 27 patients were left after exclusion of 43 flawed data points. The mean difference in OH between both BCM devices was 0.548 L (higher for version 3.2.5). Analysis of impedance data revealed differences in the high-frequency spectrum, quantifiable by the intracellular resistance, Ri (median Ri version 3.2.5 = 1750.3 Ω; Ri version 3.3.3 = 1612.45 Ω; P < 0.001), and the time delay, Td (median Td version 3.2.5 = 1.85 ns; Td version 3.3.3 = 8.88 nanoseconds; P < 0.001).
This study finds that results between the two versions of the BCM differed in a clinically meaningful fashion and that the newer version 3.3.3 device had a bias toward less OH. Circulating BCM devices should be checked for versions and only devices of the same version should be used for each patient to ensure better within-patient consistency.
Journal Article
Persister state-directed transitioning and vulnerability in melanoma
Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5B
high
cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5B
high
persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(–)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.
Slow-cycling melanoma persister cells are characterised by a high, reversible expression of H3K4 demethylase KDM5B. Here, the authors use genetic and chemical methods to enforce a permanent high expression of KDM5B and show that these cells transit to a melanocytic differentiated state and undergo cell cycle arrest.
Journal Article
HIV Treatment Knowledge in the Context of “Treatment as Prevention” (TasP)
According to 2012 universal ART guidelines, as part of “treatment as prevention” (TasP), all people living with HIV (PLWH) should immediately initiate antiretroviral therapy post-diagnosis to facilitate viral suppression. PLWH who are virally suppressed have no risk of sexually transmitting HIV. This study used descriptive analysis of quantitative data (N = 99) and thematic analysis of qualitative interviews (n = 36) to compare participants recruited from a hospital-based detoxification (detox) unit, largely diagnosed with HIV pre-2012 (n = 63) vs. those recruited from public, urban sexual health clinics (SHCs), mainly diagnosed in 2012 or later (n = 36). Detox participants were significantly more knowledgeable than SHC participants about HIV treatment, except regarding TasP. SHC participants’ desire for rapid linkage to care and ART initiation was in line with 2012 universal ART guidelines and TasP messaging regarding viral suppression. More targeted messaging to PLWH pre-2012 could ensure that all PLWH benefit from scientific advances in HIV treatment.
Journal Article
Durable Viral Suppression Among People with HIV and Problem Substance Use in the Era of Universal Antiretroviral Treatment
This study explored factors associated with durable viral suppression (DVS) among two groups of people living with HIV (PLWH) and problem substance use in the context of universal antiretroviral treatment initiation. Participants (N = 99) were recruited between 2014–2017 from public sexual health clinics [SHC] and a hospital detoxification unit [detox]). DVS (NYC HIV surveillance registry) was defined as two consecutive viral load tests ≤ 200 copies/mL, ≤ 90 days apart, with all other viral loads suppressed over 12 or 18 months. Detox participants were significantly older, with more unstable housing/employment, substance use severity, and longer-term HIV vs. SHC participants. Older age, opioid and stimulant use disorder were significantly associated with lower odds of DVS, while fulltime employment and stable housing were significantly associated with higher odds of DVS at 12-month follow-up. Patterns held at 18-month follow-up. Co-located substance use and HIV services, funding for supportive housing, and collaborative patient-provider relationships could improve DVS among populations with the syndemic of problem substance use, poverty, and long-term HIV.
Journal Article