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  1. Article ; Online: Prospects and Challenges for T Cell-Based Therapies of HCC

    Norman Woller / Sophie Anna Engelskircher / Thomas Wirth / Heiner Wedemeyer

    Cells, Vol 10, Iss 1651, p

    2021  Volume 1651

    Abstract: The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes ... ...

    Abstract The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.
    Keywords immune checkpoint inhibition ; hepatocellular carcinoma ; tumor surveillance ; immunotherapy ; T cell responses ; treatment failure ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Combination of everolimus and low-dose tacrolimus controls histological liver allograft injury as sufficiently as high-dose tacrolimus

    Emily A. Bosselmann / Fabian Dranicki / Alejandro Campos-Murguia / Björn Hartleben / Heiner Wedemeyer / Elmar Jaeckel / Richard Taubert

    Frontiers in Transplantation, Vol

    2023  Volume 2

    Abstract: IntroductionThe combination of everolimus (EVR) and low-dose tacrolimus (lowTAC) prevents T cell-mediated rejection of liver grafts as sufficiently as high-dose tacrolimus (highTAC) and mycophenolate, but is associated with a preserved kidney function ... ...

    Abstract IntroductionThe combination of everolimus (EVR) and low-dose tacrolimus (lowTAC) prevents T cell-mediated rejection of liver grafts as sufficiently as high-dose tacrolimus (highTAC) and mycophenolate, but is associated with a preserved kidney function within the first years after orthotopic liver transplantation (OLT). However, none of the available studies assessed the histological pattern of graft injury or fibrosis in surveillance biopsies (svLbx).MethodsAll svLbx taken under at least one month of stable immunosuppression with either EVR (aim 3-8 ng/ml) combined with lowTAC (aim 3-5 ng/ml) or highTAC (aim 5-8 ng/ml) combined with mycophenolate (500-1500 mg/day) within the first three to four years after OLT at our center were included. Patients who were switched to EVR because of insufficient control of alloreactivity were excluded.ResultsReasons for switches to EVR were mainly malignancies before or after OLT, or chronic kidney injury. We were able to include 20 svLbx with EVR/lowTAC and 49 with highTAC/mycophenolate. Both groups had similar liver enzymes and similar kidney function. The EVR/lowTAC group exhibited lower TAC trough levels at svLbx (4.4 vs. 6.6 ng/ml; p<.001) in comparison to highTAC/mycophenolate. Histological graft injury quantified by the rejection activity index and hepatitis activity index (Ishak), as well as fibrosis were not significantly different between the EVR/lowTAC and highTAC/mycophenolate groups. Likewise, subclinical TCMR, histological criteria justifying immunosuppression minimization, and steatosis had equal prevalence in both regimens. Immunosuppression was adjusted according to the svLbx findings. Immunosuppression regimens had similarly low rates of rejection after immunosuppression reduction, when relevant graft injury was absent in the biopsy.DiscussionIn conclusion, EVR/lowTAC seems to control alloreactivity and histological graft injury as sufficiently as highTAC/mycophenolate within the first 3-4 years after OLT.
    Keywords graft injury ; fibrosis ; mTOR inhibitor ; everolimus ; immunosuppression ; tacrolimus ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Additional challenges in reaching hepatitis C elimination goals in Germany due to the COVID-19 pandemic - descriptive analysis of drug prescription data from January 2018 to June 2021

    Emily D. Meyer / Sandra Dudareva / Christian Kollan / Stefan Mauss / Heiner Wedemeyer / Daniel Schmidt / Ruth Zimmermann

    Frontiers in Public Health, Vol

    2023  Volume 11

    Abstract: Effectively treating hepatitis C viral (HCV) infections prevents sequelae and onward transmission. In Germany, HCV drug prescriptions have declined since 2015. During the COVID-19 pandemic, lockdowns impacted the access to HCV care services and HCV ... ...

    Abstract Effectively treating hepatitis C viral (HCV) infections prevents sequelae and onward transmission. In Germany, HCV drug prescriptions have declined since 2015. During the COVID-19 pandemic, lockdowns impacted the access to HCV care services and HCV treatment. We assessed if the COVID-19 pandemic further decreased treatment prescriptions in Germany. We built log-linear models with monthly HCV drug prescription data from pharmacies from January 2018 - February 2020 (pre-pandemic) to calculate expected prescriptions for March 2020-June 2021 and different pandemic phases. We calculated monthly prescription trends per pandemic phase using log-linear models. Further, we scanned all data for breakpoints. We stratified all data by geographic region and clinical settings. The number of DAA prescriptions in 2020 (n = 16,496, −21%) fell below those of 2019 (n = 20,864) and 2018 (n = 24,947), continuing the declining trend from previous years. The drop in prescriptions was stronger from 2019 to 2020 (−21%) than from 2018 to 2020 (−16%). Observed prescriptions met predictions from March 2020 to June 2021, but not during the first COVID-19 wave (March 2020–May 2020). Prescriptions increased during summer 2020 (June 2020-September 2020) and fell below the pre-pandemic numbers during the following pandemic waves (October 2020 – February 2021 and March 2021 – June 2021). Breakpoints during the first wave indicate that prescriptions plummeted overall, in all clinical settings and in four of six geographic regions. Both, outpatient clinics and private practices prescribed overall as predicted. However, outpatient hospital clinics prescribed 17–39% less than predicted during the first pandemic wave. HCV treatment prescriptions declined but stayed within the lower realms of predicted counts. The strongest decline during the first pandemic wave indicates a temporary HCV treatment gap. Later, prescriptions matched predictions despite of pronounced decreases during the second and third waves. In future pandemics, clinics and private ...
    Keywords hepatitis C ; COVID-19 ; delivery of health care ; Agenda 2030 ; antiviral agents - therapeutic use ; Public aspects of medicine ; RA1-1270
    Subject code 360
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Evaluation of immunoserological detection of anti-liver kidney microsomal, anti-soluble liver antigen and anti-mitochondrial antibodies

    Alejandro Campos-Murguia / Nicole Henjes / Stephanie Loges / Heiner Wedemeyer / Elmar Jaeckel / Richard Taubert / Bastian Engel

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract Autoantibodies are the diagnostic hallmark of autoimmune liver diseases. Indirect immunofluorescence (IFT) is the reference method for the detection of anti-mitochondrial antibodies (AMA) and anti-liver kidney microsomal type-1 (anti-LKM1) ... ...

    Abstract Abstract Autoantibodies are the diagnostic hallmark of autoimmune liver diseases. Indirect immunofluorescence (IFT) is the reference method for the detection of anti-mitochondrial antibodies (AMA) and anti-liver kidney microsomal type-1 (anti-LKM1) antibodies, and inhibition ELISA (iELISA) for anti-soluble liver antigen (anti-SLA) antibodies. Given the complexity of these techniques, commercial ELISAs have emerged as a practical alternative, but without head-to-head validations. This study evaluated the agreement between three commercial ELISAs and the reference techniques and the impact of polyreactive immunoglobulin G (pIgG), a recently described phenomenon in autoimmune hepatitis, on commercial ELISAs. Inter-rater reliability was assessed using Cohen-Kappa coefficient (κ). Forty-eight, 46, and 66 samples were analyzed for AMA, anti-LKM1, and anti-SLA, respectively. For AMA, one commercial assay showed high agreement (κ = 0.91 (0.78–1.00)) with the reference method, while the other two showed weak or moderate agreement. For anti-LKM1, only one commercial assay showed high agreement (κ = 0.86 (0.71–1.0)). For anti-SLA antibodies only moderate agreement was achieved (κ up to 0.71 (0.52–0.89)). There was a trend towards higher pIgG levels in false-positives in the commercial ELISAs. Patients with high suspicion of autoimmune liver diseases should be referred to reference laboratories with the capacity of performing gold standard methods if the initial ELISA-based screening was performed.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Controlled Attenuation Parameter Is Associated with a Distinct Systemic Inflammatory Milieu after Clearance of HCV Infection

    Yanqin Du / Tanvi Khera / Zhaoli Liu / Magdalena Tudrujek-Zdunek / Anna Dworzanska / Markus Cornberg / Cheng-Jian Xu / Krzysztof Tomasiewicz / Heiner Wedemeyer

    Biomedicines, Vol 11, Iss 1529, p

    2023  Volume 1529

    Abstract: Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects along with a high prevalence of hepatic steatosis. After HCV clearance, steatosis persists in many patients. However, the reasons behind this phenomenon are not ... ...

    Abstract Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects along with a high prevalence of hepatic steatosis. After HCV clearance, steatosis persists in many patients. However, the reasons behind this phenomenon are not completely clear. To investigate the association between 92 soluble inflammatory mediators (SIMs) and the steatosis grade, we made use of a cohort of 94 patients with chronic HCV infection who cleared HCV after direct-acting antiviral agent (DAA) treatment. Patients were classified into three groups according to their controlled attenuation parameter (CAP). CAP is associated with ALT, γ-GT and liver stiffness after HCV clearance. While stem cell factor (SCF) and tumor necrosis factor ligand superfamily member 12 (TWEAK) levels were significantly reduced in patients with CAP > 299 dB/m, the levels of fibroblast growth factor (FGF)-21 and interleukin-18 receptor 1 (IL-18R1) were higher in those patients at week 96 after virus clearance. These four markers also showed a linear correlation with CAP values. FGF-21 levels correlated with CAP only after HCV clearance. Taken together, these four biomarkers, namely SCF, TWEAK, FGF-21 and IL-18R1, are associated with CAP status after virus clearance. A potential role of these proteins in the pathogenesis of post-sustained viral response (SVR) nonalcoholic steatohepatitis requires further investigation.
    Keywords steatosis ; chronic hepatitis C virus ; sustained viral response ; soluble inflammatory mediators ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Hepatitis E In Transplant Recipients

    Sven Pischke / Heiner Wedemeyer

    EBioMedicine, Vol 2, Iss 11, Pp 1564-

    Why Is This Not A Problem In Japan?

    2015  Volume 1565

    Keywords Medicine ; R ; Medicine (General) ; R5-920
    Language English
    Publishing date 2015-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Nosocomial infections in female compared with male patients with decompensated liver cirrhosis

    Marie Griemsmann / Tammo L. Tergast / Nicolas Simon / Abdul-Rahman Kabbani / Michael P. Manns / Heiner Wedemeyer / Markus Cornberg / Benjamin Maasoumy

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 10

    Abstract: Abstract There are considerable differences between males and females regarding the etiology, progression and outcome of liver diseases. Infections are a frequent and severe complication in these patients. This study aimed to examine sex specific ... ...

    Abstract Abstract There are considerable differences between males and females regarding the etiology, progression and outcome of liver diseases. Infections are a frequent and severe complication in these patients. This study aimed to examine sex specific differences in the incidence and clinical course of nosocomial infections in patients with decompensated liver cirrhosis. A number of 556 consecutive hospitalized patients with decompensated liver cirrhosis and ascites were analyzed. The patients were followed up for the incidence of nosocomial infections, acute kidney injury (AKI), acute-on-chronic liver failure (ACLF) as well as liver transplantation and death (LTx-free survival). A number of 285 patients (111 women and 174 men) developed a nosocomial infection. Incidence was numerically lower in men (P = 0.076). While the frequency of a nosocomial spontaneous bacterial peritonitis was similar between males and females, the incidence of a nosocomial urinary tract infection was significantly higher in women (P < 0.001). No sex specific differences were documented regarding the outcome of an infection as indicated by a similar incidence of, AKI, ACLF as well as LTx-free survival. There seem to be no major differences in the incidence and outcome of nosocomial infections between male and female patients.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Comprehensive Evaluation of Hepatitis E Serology and Molecular Testing in a Large Cohort

    Olympia E. Anastasiou / Viktoria Thodou / Annemarie Berger / Heiner Wedemeyer / Sandra Ciesek

    Pathogens, Vol 9, Iss 2, p

    2020  Volume 137

    Abstract: Introduction: Reliable and cost-effective diagnostics for hepatitis E virus (HEV) infection are necessary. The aim of our study was to investigate which diagnostic test is most accurate to detect HEV infection in immunocompetent and immunosuppressed ... ...

    Abstract Introduction: Reliable and cost-effective diagnostics for hepatitis E virus (HEV) infection are necessary. The aim of our study was to investigate which diagnostic test is most accurate to detect HEV infection in immunocompetent and immunosuppressed patients in a real world setting. Patients and Methods: We performed a retrospective analysis of 1165 patients tested for HEV antibodies and HEV PCR at the same time point. Clinical, laboratory and virological data were taken from patient charts. HEV IgA was measured in a subgroup of 185 patients. Results: HEV RNA was detectable in 61 patients (5.2%); most of them (n = 49, 80.3%/n = 43, 70.5%) were HEV IgM+ and IgG+; however, 12 patients (19.6%) were HEV RNA positive/HEV IgM negative and 17 patients (27.8%) were HEV RNA positive/HEV IgG negative. Ten HEV RNA positive patients (16.4%) had neither HEV IgG nor IgM antibodies. Importantly, all of them were immunosuppressed. HEV IgA testing was less sensitive than HEV IgM for HEV diagnosis. Conclusions: HEV infection can be overlooked in patients without HEV specific antibodies. Performing PCR is necessary to diagnose or exclude HEV infection in immunocompromised hosts. In immunocompetent patients, a screening based on HEV antibodies (IgG/IgM) is sufficient.
    Keywords hepatitis e ; hev ; serology ; pcr ; immunosuppression ; Medicine ; R
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Irreversible impact of chronic hepatitis C virus infection on human natural killer cell diversity

    Benedikt Strunz / Julia Hengst / Heiner Wedemeyer / Niklas K. Björkström

    Cell Stress, Vol 2, Iss 8, Pp 216-

    2018  Volume 218

    Abstract: Diversity is crucial for the immune system to efficiently combat infections. Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to the control of viral infections. NK cells were for long thought to be a homogeneous population of ... ...

    Abstract Diversity is crucial for the immune system to efficiently combat infections. Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to the control of viral infections. NK cells were for long thought to be a homogeneous population of cells. However, recent work has instead revealed NK cells to represent a highly diverse population of immune cells where a vast number of subpopulations with distinct characteristics exist across tissues. However, the degree to which a chronic viral infection affects NK cell diversity remains elusive. Hepatitis C virus (HCV) is effective in establishing chronic infection in humans. During the last years, new direct-acting antiviral drugs (DAA) have revolutionized treatment of chronic hepatitis C, enabling rapid cure in the majority of patients. This allows us to study the influence of a chronic viral infection and its subsequent elimination on the NK cell compartment with a focus on NK cell diversity. In our recent study (Nat Commun, 9:2275), we show that chronic HCV infection irreversibly impacts human NK cell repertoire diversity.
    Keywords Hepatitis C virus infection ; direct-acting antiviral therapy ; natural killer cells ; Medicine ; R ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-07-01T00:00:00Z
    Publisher Shared Science Publishers OG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: The role of zinc in liver cirrhosis

    Kurt Grüngreiff / Dirk Reinhold / Heiner Wedemeyer

    Annals of Hepatology, Vol 15, Iss 1, Pp 7-

    2016  Volume 16

    Abstract: Zinc is an essential trace element playing fundamental roles in cellular metabolism. It acts mostly by binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. ... ...

    Abstract Zinc is an essential trace element playing fundamental roles in cellular metabolism. It acts mostly by binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Zinc is critical to a large number of structural proteins, enzymatic processes, and transcription factors. Zinc deficiency can result in a spectrum of clinical manifestations, such as poor of appetite, loss of body hair, altered taste and smell, testicular atrophy, cerebral and immune dysfunction, and diminished drug elimination capacity. These are common symptoms in patients with chronic liver diseases, especially liver cirrhosis. The liver is the main organ responsible for the zinc metabolism which can be affected by liver diseases. On the other hand, zinc deficiency may alter hepatocyte functions and also immune responses in inflammatory liver diseases. Liver cirrhosis represents the most advanced stage of chronic liver diseases and is the common outcome of chronic liver injury. It is associated with energy malnutrition, with numerous metabolic disorders, such as hypoalbuminemia, with imbalance between branched-chain amino acids and aromatic amino acids, and with reduced zinc serum concentrations. All these processes can influence the clinical outcome of patients, such ascites, hepatic encephalopathy and hepatocellular carcinoma. In the present review, we summarize the emerging evidence on the pitoval role of zinc in the pathogenesis of liver cirrhosis.
    Keywords Zinc deficiency ; Cirrhosis complications ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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