Liver fibrosis and cirrhosis resulting from long-standing liver damage represents a major health care burden worldwide. To date, there is no anti-fibrogenic agent available, making liver ...transplantation the only curative treatment for decompensated cirrhotic liver disease. Liver fibrosis can result from different underlying chronic liver disease, such as chronic viral infection, excessive alcohol consumption, fatty liver disease or autoimmune liver diseases. It is becoming increasingly recognised that as a result from different pathogenic mechanisms liver fibrosis must be considered as many different diseases for which individual treatment strategies need to be developed. Moreover, the pathogenic changes of both liver architecture and vascularisation in cirrhotic livers, as well as the lack of “true-to-life” in vitro models have impeded the development of an effective anti-fibrogenic drug. Thus, in order to identify an efficient anti-fibrogenic compound, novel in-vitro models mimicking the interplay between pro-fibrogenic cell populations, immune cells and, importantly, the extracellular matrix need to be developed.
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Ultrashort pulse laser processing can result in the secondary generation of unwanted X-rays if a critical laser irradiance of about 10
W cm
is exceeded. Spectral X-ray emissions were investigated ...during the processing of tungsten and steel using three complementary spectrometers (based on CdTe and silicon drift detectors) simultaneously for the identification of a worst-case spectral scenario. Therefore, maximum X-ray photon energies were determined, and corresponding dose equivalent rates were calculated. An ultrashort pulse laser workstation with a pulse duration of 274 fs, a center wavelength of 1030 nm, pulse repetition rates between 50 kHz and 200 kHz, and a Gaussian laser beam focused to a spot diameter of 33 μm was employed in a single pulse and burst laser operation mode. Different combinations of laser pulse energy and repetition rate were utilized, keeping the average laser power constant close to the maximum power of 20 W. Peak irradiances
ranging from 7.3 × 10
W cm
up to 3.0 × 10
W cm
were used. The X-ray dose equivalent rate increases for lower repetition rates and higher pulse energy if a constant average power is used. Laser processing with burst mode significantly increases the dose rates and the X-ray photon energies. A maximum X-ray photon energy of about 40 keV was observed for burst mode processing of tungsten with a repetition rate of 50 kHz and a peak irradiance of 3 × 10
W cm
.
Atezolizumab/bevacizumab (atezo/bev) and lenvatinib have demonstrated efficacy as first-line therapies for hepatocellular carcinoma (HCC). However, vascular endothelial growth factor (VEGF) ...inhibition with these therapies may be associated with the risk of bleeding and thromboembolic events. In this study, we evaluated the efficacy and safety with focus on the bleeding and thromboembolic events of atezo/bev vs. lenvatinib in a large, multicenter real-world population.
This study is based on HCC cohorts from seven centers in Germany and Austria. Incidences of bleeding or thromboembolic events and efficacy outcomes were assessed and compared.
In total, 464 patients treated with atezo/bev (n = 325) or lenvatinib (n = 139) were analyzed. Both groups were balanced with respect to demographics, presence of liver cirrhosis, and variceal status. Duration of therapy did not differ between groups. Within 3 months of therapy, bleeding episodes were described in 57 (18%) patients receiving atezo/bev compared with 15 (11%) patients receiving lenvatinib (p = 0.07). Variceal hemorrhage occurred in 11 (3%) patients treated with atezo/bev compared with 4 (3%) patients treated with lenvatinib (p = 0.99). Thromboembolic events were reported in 19 (6%) of patients in the atezo/bev cohort compared with 5 (4%) patients in the lenvatinib cohort (p = 0.37). In addition, incidence of overall bleeding, variceal hemorrhage, and thromboembolic events did not differ significantly in patients who received either atezo/bev or lenvantinib for 6 months.
Safety considerations related to bleeding and thromboembolic events may not be helpful in guiding clinical decision-making when choosing between atezo/bev and lenvatinib.
The inhibition of VEGF by current first-line therapies for HCC, such as atezolizumab/bevacizumab or lenvatinib, may be associated with the risk of bleeding and thromboembolic events. Studies comparing the incidence of these side effects between atezolizumab/bevacizumab and lenvatinib, which are preferred treatments over sorafenib for HCC, are needed. Differences in this side effect profile may influence the choice of first-line therapy by treating physicians. Because no significant differences were observed regarding bleeding or thromboembolic events between both therapies in the present study, we conclude that safety considerations related to these events may not be helpful in guiding clinical decision-making when choosing between atezolizumab/bevacizumab and lenvatinib.
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•Evaluation of the efficacy and safety of atezolizumab/bevacizumab and lenvatinib in a large real-world population of 464 patients with HCC.•Compared with lenvatinib, atezolizumab/bevacizumab improves ORR.•No significant differences in bleeding or thromboembolic events were observed.•In atezolizumab/bevacizumab-treated patients, spleen size and history of variceal bleeding were associated with GI-bleeding risk, while anticoagulation was associated with non-GI bleeding risk.
Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune‐mediated liver damage. In this study, we addressed the question whether ...mucosal‐associated invariant T (MAIT) cells, innate‐like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon‐γ (IFN‐γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA‐DR, and CTLA‐4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)‐12 and IL‐18, leading to decreased IFN‐γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL‐12 further resulted in expression of the profibrogenic cytokine IL‐17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL‐17. Conclusion: Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC‐mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172‐186).
Die Digitalisierung der Wirtschaft stellt Führungskräfte und die Managementweiterbildung vor neue Herausforderungen. Um Nachwuchsführungskräfte in der professionellen Weiterbildung auf diese ...Herausforderungen vorzubereiten, werden in diesem Beitrag entsprechende Kompetenzen abgeleitet: Aufbauend auf etablierten sowie modernen Erkenntnissen der Managementforschung werden relevante Kompetenzbereiche definiert. Ergänzt werden Inhalte aus der aktuellen Diskussion um die so genannte Digitale Führung. Zudem werden die Perspektive von Arbeitgeber_innen sowie Ergebnisse aus der Forschung zur Beschäftigungsfähigkeit integriert. Diese theoretischen Erkenntnisse werden abschließend durch Expert_inneninterviews mit Personalentscheider_innen aus der Berliner Digitalszene validiert. Im Ausblick dienen diese Kompetenzen als Rahmen für die Entwicklung von Weiterbildungsprogrammen für Nachwuchsführungskräfte an der Berlin Professional School. (DIPF/Orig.)
When machining difficult‐to‐cut, nonferrous materials, chemical vapor deposited (CVD) diamond–coated cutting tools are applied. The tools’ favorable mechanical property profile is based on the ...hardness of the coating as well as the adaptability of the substrate. Nevertheless, the reproducibility of machining results and process stability are limited by insufficient coating adhesion. The resulting cutting tool failure is based on coating delamination initiated by crack development. By assessing residual stress as an influence of coating adhesion, an analysis of CVD diamond–coated tools is performed using synchrotron X‐ray diffraction in transmission geometry. Investigation of a nanocrystalline and multilayer morphology on cobalt‐based tungsten carbide (WC‐Co) and a silicon nitride–based ceramic (Si3N4) provides the distribution of the principal in‐plane residual stress tensor component σ22 depending on the coating morphology and substrate material. Contrary to microcrystalline CVD diamond, nanocrystalline layers decrease the compressive residual stress. In addition, the CVD diamond coating deposited on the Si3N4 substrate material tends to induce an overall initial tensile residual stress that leads to increased tool performance compared to WC‐Co‐based coated tools. Variation of the coating morphology as well as the substrate material offers the possibility to extend the current model for residual stress–dependent tool failure.
Based on a novel approach by using synchrotron X‐ray diffraction in transmission geometry, a detailed investigation of the principal residual stress state of chemical vapor depositioned diamond coated cutting tools was performed. For varying cutting tool specifications, differing principal residual stress was documented and subsequently correlated with the respected cutting tool application of CFRP machining.
Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, ...characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.
Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence ...suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known
or
mutations on primary human HSC activation, proliferation, and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hepatic stellate cell (hHSC) proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (
) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Data mining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (
) and AMPKα2 (
) expression differed depending on the mutation (
or
), tumor grading, and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumor-promoting interactions between hHSC and HCC.
HCC is marked by genetic heterogeneity and activated hepatic stellate cells (HSC) are considered key players during HCC development. The paracrine effect of different HCC cell lines on the activation of primary hHSC was accompanied by differential AMPK activation depending on the HCC line used. Pharmacological treatment inhibited the HCC-induced hHSC activation through AMPK-dependent and AMPK-independent mechanisms. This heterogenic effect on HCC-induced AMPK activation was confirmed by data mining TCGA and LICA-FR databases.
During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although ...error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell-specific inactivation of the critical HR factor
, we detected decreased proliferation, survival, and thereby class switching of ex vivo-activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in
-deficient mice. These mutation pattern changes in
-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.
: We have used the human ECV 304 cell line to study the origin and fate of extracellular RNA (exRNA) in cell culture. Quantification of different extracellular RNA species using reverse ...transcription followed by quantitative PCR revealed a prevalent fraction of ribosomal RNAs. Comparison of intracellular and extracellular ribosomal RNA copy numbers allowed the calculation of the number of destroyed cells that would result in the corresponding number of extracellular rRNAs. Interestingly, this number was comparable to the amount of destroyed cells as determined by the measurement of extracellular lactate dehydrogenase activity.
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