Publications by authors named "Johannes Haybaeck"

221 Publications

Autophagy in α-Synucleinopathies-An Overstrained System.

Cells 2021 Nov 12;10(11). Epub 2021 Nov 12.

Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria.

Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
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http://dx.doi.org/10.3390/cells10113143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618716PMC
November 2021

Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC).

Cancers (Basel) 2021 Nov 11;13(22). Epub 2021 Nov 11.

Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Intestinal-type adenocarcinoma (ITAC) is a rare cancer of the nasal cavity and paranasal sinuses that occurs sporadically or secondary to exposure to occupational hazards, such as wood dust and leather. Eukaryotic translation initiation factors have been described as promising targets for novel cancer treatments in many cancers, but hardly anything is known about these factors in ITAC. Here we performed in silico analyses, evaluated the protein levels of EIF2S1, EIF5A and EIF6 in tumour samples and non-neoplastic tissue controls obtained from 145 patients, and correlated these results with clinical outcome data, including tumour site, stage, adjuvant radiotherapy and survival. In silico analyses revealed significant upregulation of the translation factors EIF6 (ITGB4BP), EIF5, EIF2S1 and EIF2S2 ( < 0.05) with a higher arithmetic mean expression in ITAC compared to non-neoplastic tissue (NNT). Immunohistochemical analyses using antibodies against EIF2S1 and EIF6 confirmed a significantly different expression at the protein level ( < 0.05). In conclusion, this work identifies the eukaryotic translation initiation factors EIF2S1 and EIF6 to be significantly upregulated in ITAC. As these factors have been described as promising therapeutic targets in other cancers, this work identifies candidate therapeutic targets in this rare but often deadly cancer.
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http://dx.doi.org/10.3390/cancers13225649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616251PMC
November 2021

Hepatic Response of Magnesium-Restricted Wild Type Mice.

Metabolites 2021 Nov 6;11(11). Epub 2021 Nov 6.

International Biobank and Education, Medical University of Graz, 8036 Graz, Austria.

Magnesium-deficiency is implicated in many metabolic disorders, e.g., type 2 diabetes and metabolic syndrome, representing risk factors for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the contribution of magnesium-restriction to the development of NAFLD. Magnesium-deficiency was induced in C57BL/6 mice by feeding a magnesium-deficient-diet. Metabolic markers as well as markers of inflammation and liver function were assessed. Furthermore, liver tissue was examined histopathologically and compared with specimens from high-fat-diet fed and control mice. Finally, the hepatic inflammatory response was quantified by determining hepatic IL-6, TNFα, and MCP-1. Magnesium-restriction resulted in at least a 2-fold significant reduction of serum magnesium levels compared to the high-fat-diet fed and control mice, whereas the hepatic magnesium content was decreased due to high-fat-diet feeding. No changes in metabolic markers in magnesium-restricted mice were observed, while the cholesterol content was elevated in high-fat-diet fed mice. Magnesium-restricted mice additionally featured inflammation and enlarged hepatocytes in liver histology. Furthermore, magnesium-restricted and high-fat-diet fed mice exhibited elevated hepatic TNFα levels compared to control mice. Accordingly, our data suggest that magnesium is involved in hepatic inflammatory processes and hepatocyte enlargement, key histological features of human NAFLD, and may therefore contribute to development and progression of the disease.
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http://dx.doi.org/10.3390/metabo11110762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625093PMC
November 2021

Adipocyte STAT5 deficiency does not affect blood glucose homeostasis in obese mice.

PLoS One 2021 24;16(11):e0260501. Epub 2021 Nov 24.

Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

The aim of this study was to investigate whether the lack of signal transducer and activator of transcription 5 (STAT5) in mature adipocytes of obese mice (Stat5Adipoq mice) improves glucose and lipid metabolism as previously observed in lean mice. Male Stat5Adipoq mice and their wild type (WT) littermates were fed high-fat diet (HFD). Effects of adipocyte STAT5 deficiency on adiposity as well as on glucose and lipid metabolism were determined under ad libitum feeding and after weight loss induced by calorie restriction. Compared to WT mice, obese Stat5Adipoq mice showed modestly accelerated weight gain and blunted depletion of fat stores under calorie restriction (reduction in % body fat after 3 weeks: WT, -9.3±1.1, vs Stat5Adipoq, -5.9±0.8, p = 0.04). No differences were observed between Stat5Adipoq and WT mice with regard to parameters of glucose and lipid metabolism including basal glycaemia, glucose tolerance, and plasma triglycerides. In conclusion, STAT5 deficiency in the adipocyte of HFD-fed obese mice was associated with increased fat accumulation. In contrast to previous findings in lean mice, however, lipid accumulation was not associated with any improvement in glucose and lipid metabolism. Our results do not support adipocyte STAT5 as a promising target for the treatment of obesity-associated metabolic derangements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260501PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612524PMC
November 2021

The impact of G protein-coupled oestrogen receptor 1 on male breast cancer: a retrospective analysis.

Contemp Oncol (Pozn) 2021 14;25(3):204-212. Epub 2021 Oct 14.

Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Introduction: The G protein-coupled oestrogen receptor 1 (GPER-1) is a potential prognostic marker in breast cancer. However, its role in male breast cancer (MBC) is still unknown. This study evaluates the expression of GPER-1 in MBC samples and correlates these data with clinical and pathological parameters including patients' survival.

Material And Methods: For this retrospective analysis of a prospectively maintained cohort of patients with MBC, we examined 161 specimens for GPER-1 expression using immunohistochemistry. An immunoreactive score (IRS) was calculated based on staining intensity and the percentage of positive tumour cells. Then, we correlated GPER-1 IRS with clinical and pathological parameters, and overall and relapse-free survival.

Results: About 40% of MBC samples were positive for GPER-1 expression (IRS ≥ 4). There was no significant correlation with clinicopathological parameters, such as hormone receptor status or grading. However, a statistical trend was observed for tumour size (≥ 2 cm, = 0.093). Kaplan-Meier survival analysis revealed no significant correlation with relapse-free survival. However, there was a significant correlation with overall survival, but when we adjusted the log-rank -value to compensate for the cut-off point optimization method, it rose above 0.1. Additionally, GPER-1-positive patients were older at diagnosis. When adjusted for age by multivariable Cox regression analysis, the significance of GPER-1 status for survival was further reduced.

Conclusions: We found no significant prognostic value of GPER-1 in this MBC cohort as anticipated from studies on female BC. Future studies with higher sample size are needed to further verify a potential sex-specific role of GPER-1.
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http://dx.doi.org/10.5114/wo.2021.110010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547179PMC
October 2021

Translational Regulation in Hepatocellular Carcinogenesis.

Drug Des Devel Ther 2021 14;15:4359-4369. Epub 2021 Oct 14.

Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, 6020, Austria.

The mortality of hepatocellular carcinoma (HCC) is distributed unevenly worldwide. One of the major causes is hepatitis B or hepatitis C virus infection and the development and progression of liver cirrhosis. The carcinogenesis of HCC is among others regulated via the mTOR (mechanistic target of rapamycin) signaling pathway and represents a possible method of targeted treatment. The aim of our article was to address the most recent clinical advances and findings of basic studies on the mTOR signaling pathway and the involved factors. Risk factors play a key role in dysregulation of the signaling pathway, where both mTORCs are upregulated and protein synthesis is altered. eIFs and, to a lesser extent, eEFs play an essential role in this process. Whether the factor will be upregulated or downregulated, among others, depends on hepatitis B/C virus infection. The amount of a particular factor in a patient sample lets us know whether HCC recurrence will occur, what is the likelihood of chemoresistance, and what outcome is predicted for patients with an increased value. Our analysis shows that in addition to mTOR, eIF3, eIF4, and eIF5 play an important role, as they can serve as biomarkers for non- and virus-related HCC.
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http://dx.doi.org/10.2147/DDDT.S255582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523516PMC
October 2021

SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target.

Cancers (Basel) 2021 Sep 30;13(19). Epub 2021 Sep 30.

UCL Cancer Institute, University College London, London WC1E 6BT, UK.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein-Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy.
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http://dx.doi.org/10.3390/cancers13194944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508244PMC
September 2021

Premorbid de novo artistic creativity in frontotemporal dementia (FTD) syndromes.

J Neural Transm (Vienna) 2021 Dec 7;128(12):1813-1833. Epub 2021 Oct 7.

Clinical Neuroanatomy, Department of Neurology, University Hospital, Ulm University, Ulm, Germany.

The emergence of new artistic activities or shifts in artistic style in patients with frontotemporal dementia (FTD) syndromes is well documented at or after disease onset. However, a closer look in the literature reveals emerging artistic creativity also before FTD onset, although the significance and underlying pathology of such creative endeavors remain elusive. Here, we systematically review relevant studies and report an additional FTD case to elaborate on artistic activities that developed years before disease manifestation by paying particular attention to the sequence of events in individual patients' biography and clinical history. We further discuss the FTD patient's creative activities in the context of their life events, other initial or "premorbid" dementia symptoms or risk factors described in the literature such as mental illness and mild behavioral impairment (MBI), as well as changes in neuronal systems (i.e., neuroimaging and neuropathology). In addition to our FTD patient, we identified five published cases with an FTD syndrome, including three with FTD, one with primary progressive aphasia (PPA), and one with the behavioral variant of PPA (bvPPA). Premorbid novel creativity emerged across different domains (visual, musical, writing), with the FTD diagnosis ensuing artistic productivity by a median of 8 years. Data on late-life and pre-dementia life events were available in four cases. The late creative phase in our case was accompanied by personality changes, accentuation of personality traits, and cessation of painting activities occurred with the onset of memory complaints. Thus, premorbid personality changes in FTD patients can be associated with de novo creative activity. Stressful life events may also contribute to the burgeoning of creativity. Moreover, primary neocortical areas that are largely spared by pathology at early FTD stages may facilitate the engagement in artistic activities, offering a window of opportunity for art therapy and other therapeutic interventions during the MBI stage or even earlier.
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http://dx.doi.org/10.1007/s00702-021-02426-9DOI Listing
December 2021

Correction to: Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy.

J Neural Transm (Vienna) 2021 Oct;128(10):1495

Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

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http://dx.doi.org/10.1007/s00702-021-02412-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528741PMC
October 2021

Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis?

Int J Mol Sci 2021 Aug 19;22(16). Epub 2021 Aug 19.

Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Müllerstraße 59, 6020 Innsbruck, Austria.

Nanoparticles bearing specific targeting groups can, in principle, accumulate exclusively at lesion sites bearing target molecules, and release therapeutic agents there. However, practical application of targeted nanoparticles in the living organism presents challenges. In particular, intravasally applied nanoparticles encounter physical and physiological barriers located in blood vessel walls, blocking passage from the blood into tissue compartments. Whereas small molecules can pass out of the blood, nanoparticles are too large and need to utilize physiological carriers enabling passage across endothelial walls. The issues associated with crossing blood-tissue barriers have limited the usefulness of nanoparticles in clinical applications. However, nanoparticles do not encounter blood-tissue barriers if their targets are directly accessible from the blood. This review focuses on osteoporosis, a disabling and common disease for which therapeutic strategies are limited. The target sites for therapeutic agents in osteoporosis are located in bone resorption pits, and these are in immediate contact with the blood. There are specific targetable biomarkers within bone resorption pits. These present nanomedicine with the opportunity to treat a major disease by use of simple nanoparticles loaded with any of several available effective therapeutics that, at present, cannot be used due to their associated side effects.
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http://dx.doi.org/10.3390/ijms22168932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396227PMC
August 2021

Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy.

J Neural Transm (Vienna) 2021 Oct 28;128(10):1481-1494. Epub 2021 Jul 28.

Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger's substantial contribution.
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http://dx.doi.org/10.1007/s00702-021-02383-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528766PMC
October 2021

Deregulated glutamate to pro-collagen conversion is associated with adverse outcome in lung cancer and may be targeted by renin-angiotensin-aldosterone system (RAS) inhibition.

Lung Cancer 2021 09 16;159:84-95. Epub 2021 Jul 16.

Department of Internal Medicine V (Haematology & Oncology), Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background: The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC.

Methods: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis.

Results: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids.

Conclusion: We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.020DOI Listing
September 2021

Phosphorous Magnetic Resonance Spectroscopy and Molecular Markers in IDH1 Wild Type Glioblastoma.

Cancers (Basel) 2021 Jul 16;13(14). Epub 2021 Jul 16.

Department of Neuroradiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

The World Health Organisation's (WHO) classification of brain tumors requires consideration of both histological appearance and molecular characteristics. Possible differences in brain energy metabolism could be important in designing future therapeutic strategies. Forty-three patients with primary, isocitrate dehydrogenase 1 (IDH1) wild type glioblastomas (GBMs) were included in this study. Pre-operative standard MRI was obtained with additional phosphorous magnetic resonance spectroscopy (31-P-MRS) imaging. Following microsurgical resection of the tumors, biopsy specimens underwent neuropathological diagnostics including standard molecular diagnosis. The spectroscopy results were correlated with epidermal growth factor (EGFR) and O6-Methylguanine-DNA methyltransferase (MGMT) status. EGFR amplified tumors had significantly lower phosphocreatine (PCr) to adenosine triphosphate (ATP)-PCr/ATP and PCr to inorganic phosphate (Pi)-PCr/Pi ratios, and higher Pi/ATP and phosphomonoesters (PME) to phosphodiesters (PDE)-PME/PDE ratio than those without the amplification. Patients with MGMT-methylated tumors had significantly higher cerebral magnesium (Mg) values and PME/PDE ratio, while their PCr/ATP and PCr/Pi ratios were lower than in patients without the methylation. In survival analysis, not-EGFR-amplified, MGMT-methylated GBMs showed the longest survival. This group had lower PCr/Pi ratio when compared to MGMT-methylated, EGFR-amplified group. PCr/Pi ratio was lower also when compared to the MGMT-unmethylated, EGFR not-amplified group, while PCr/ATP ratio was lower than all other examined groups. Differences in energy metabolism in various molecular subtypes of wild-type-GBMs could be important information in future precision medicine approach.
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http://dx.doi.org/10.3390/cancers13143569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305039PMC
July 2021

RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence.

iScience 2021 Jun 24;24(6):102618. Epub 2021 May 24.

Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.

Recent data suggest that therapy-resistant quiescent cancer stem cells (qCSCs) are the source of relapse in colon cancer. Here, using colon cancer patient-derived organoids and xenografts, we identify rare long-term label-retaining qCSCs that can re-enter the cell cycle to generate new tumors. RNA sequencing analyses demonstrated that these cells display the molecular hallmarks of quiescent tissue stem cells, including expression of p53 signaling genes, and are enriched for transcripts common to damage-induced quiescent revival stem cells of the regenerating intestine. In addition, we identify negative regulators of cell cycle, downstream of p53, that we show are indicators of poor prognosis and may be targeted for qCSC abolition in both p53 wild-type and mutant tumors. These data support the temporal inhibition of downstream targets of p53 signaling, in combination with standard-of-care treatments, for the elimination of qCSCs and prevention of relapse in colon cancer.
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http://dx.doi.org/10.1016/j.isci.2021.102618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185225PMC
June 2021

The predictive potential of Neuronatin for neoadjuvant chemotherapy of breast cancer.

Cancer Biomark 2021 ;32(2):161-173

Department of Pathology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.

Background: Neuronatin (NNAT) determined by immunohistochemistry is a negative prognostic biomarker for breast cancer, independent of the major clinicopathological markers.

Objective: Here, we investigated whether NNAT is also a predictive biomarker for pathological remission after neoadjuvant chemotherapy.

Methods: One hundred and four breast cancer patients, treated with systemic neoadjuvant chemotherapy were included in this retrospective study. NNAT was detected in formaldehyde fixed, paraffin embedded primary cancer tissue by immunohistochemistry and an immuno-reactive score (IRS) determined. Pathological remission was scored according to Sinn and by evaluation of cytopathic effects. NNAT-IRS was correlated with clinicopathological parameters as well as relapse free and overall survival and for pathological remission after neoadjuvant therapy.

Results: NNAT IRS was an independent prognostic marker for relapse free and overall survival and the time from diagnosis to the "tumor-free" state. NNAT IRS was associated with Luminal-A tumors and correlated slightly negative with age and lymph-node metastasis. There was no significant correlation of NNAT-IRS with Sinn's remission score, but with cytopathic effects of chemotherapy.

Conclusions: We confirmed the prognostic impact of NNAT-IRS in an independent cohort of neoadjuvantly treated patients. Additionally, a correlation with a score for pathological remission under systemic neoadjuvant chemotherapy for breast cancer was found.
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http://dx.doi.org/10.3233/CBM-203127DOI Listing
January 2021

High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53.

Proc Natl Acad Sci U S A 2021 06;118(22)

Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany;

Specified intestinal epithelial cells reprogram and contribute to the regeneration and renewal of the epithelium upon injury. Mutations that deregulate such renewal processes may contribute to tumorigenesis. Using intestinal organoids, we show that concomitant activation of Notch signaling and ablation of p53 induce a highly proliferative and regenerative cell state, which is associated with increased levels of Yap and the histone methyltransferase Mll1. The induced signaling system orchestrates high proliferation, self-renewal, and niche-factor-independent growth, and elevates the trimethylation of histone 3 at lysine 4 (H3K4me3). We demonstrate that Yap and Mll1 are also elevated in patient-derived colorectal cancer (CRC) organoids and control growth and viability. Our data suggest that Notch activation and p53 ablation induce a signaling circuitry involving Yap and the epigenetic regulator Mll1, which locks cells in a proliferative and regenerative state that renders them susceptible for tumorigenesis.
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http://dx.doi.org/10.1073/pnas.2019699118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179171PMC
June 2021

A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy.

Cancers (Basel) 2021 Mar 23;13(6). Epub 2021 Mar 23.

Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.

Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
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http://dx.doi.org/10.3390/cancers13061482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004965PMC
March 2021

Interactome Mapping of eIF3A in a Colon Cancer and an Immortalized Embryonic Cell Line Using Proximity-Dependent Biotin Identification.

Cancers (Basel) 2021 Mar 14;13(6). Epub 2021 Mar 14.

Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany.

Translation initiation comprises complex interactions of eukaryotic initiation factor (eIF) subunits and the structural elements of the mRNAs. Translation initiation is a key process for building the cell's proteome. It not only determines the total amount of protein synthesized but also controls the translation efficiency for individual transcripts, which is important for cancer or ageing. Thus, understanding protein interactions during translation initiation is one key that contributes to understanding how the eIF subunit composition influences translation or other pathways not yet attributed to eIFs. We applied the BioID technique to two rapidly dividing cell lines (the immortalized embryonic cell line HEK-293T and the colon carcinoma cell line HCT-166) in order to identify interacting proteins of eIF3A, a core subunit of the eukaryotic initiation factor 3 complex. We identified a total of 84 interacting proteins, with very few proteins being specific to one cell line. When protein biosynthesis was blocked by thapsigargin-induced endoplasmic reticulum (ER) stress, the interacting proteins were considerably smaller in number. In terms of gene ontology, although eIF3A interactors are mainly part of the translation machinery, protein folding and RNA binding were also found. Cells suffering from ER-stress show a few remaining interactors which are mainly ribosomal proteins or involved in RNA-binding.
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http://dx.doi.org/10.3390/cancers13061293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999522PMC
March 2021

Emergent creativity in frontotemporal dementia.

J Neural Transm (Vienna) 2021 03 12;128(3):279-293. Epub 2021 Mar 12.

Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria.

Numerous papers report on connections between creative work and dementing illness, particularly in frontotemporal dementia (FTD), which may combine with motor neuron disease (FTD-MND). However, the emergence of FTD(-MND) patients' de novo artistic activities is rarely reported and underappreciated. Therefore, the present review summarizes relevant case studies' outcomes, capturing creativity's multifaceted nature. Here, we systematically searched for case reports by paying particular attention to the chronological development of individual patients' clinical symptoms, signs, and life events. We synoptically compared the various art domains to the pattern of brain atrophy, the clinical and pathological FTD subtypes. 22 FTD(-MND) patients were identified with creativity occurring either at the same time (41%) or starting after the disease onset (59%); the median lag between the first manifestation of disease and the beginning of creativity was two years. In another five patients, novel artistic activity was developed by a median of 8 years before the start of dementia symptoms. Artistic activity usually evolved over time with a peak in performance, followed by a decline that was further hampered by physical impairment during disease progression. Early on, the themes and objects depicted were often concrete and realistic, but they could become more abstract or symbolic at later stages. Emergent artistic processes may occur early on in the disease process. They appear to be a communication of inner life and may also reflect an attempt of compensation or "self-healing". The relative preservation of primary neocortical areas such as the visual, auditory, or motor cortex may enable the development of artistic activity in the face of degeneration of association cortical areas and subcortical, deeper central nervous system structures. It is crucial to understand the differential loss of function and an individual's creative abilities to implement caregiver-guided, personalized therapeutic strategies such as art therapy.
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http://dx.doi.org/10.1007/s00702-021-02325-zDOI Listing
March 2021

Interleukin-6 controls recycling and degradation, but not internalization of its receptors.

J Biol Chem 2021 Jan-Jun;296:100434. Epub 2021 Feb 19.

Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany. Electronic address:

Interleukin-6 (IL-6) is a cytokine implicated in proinflammatory as well as regenerative processes and acts via receptor complexes consisting of the ubiquitously expressed, signal-transducing receptor gp130 and the IL-6 receptor (IL-6R). The IL-6R is expressed only on hepatocytes and subsets of leukocytes, where it mediates specificity of the receptor complex to IL-6 as the subunit gp130 is shared with all other members of the IL-6 cytokine family such as IL-11 or IL-27. The amount of IL-6R at the cell surface thus determines the responsiveness of the cell to the cytokine and might therefore be decisive in the development of inflammatory disorders. However, how the expression levels of IL-6R and gp130 at the cell surface are controlled is largely unknown. Here, we show that IL-6R and gp130 are constitutively internalized independent of IL-6. This process depends on dynamin and clathrin and is temporally controlled by motifs within the intracellular region of gp130 and IL-6R. IL-6 binding and internalization of the receptors is a prerequisite for activation of the Jak/STAT signaling cascade. Targeting of gp130, but not of the IL-6R, to the lysosome for degradation depends on stimulation with IL-6. Furthermore, we show that after internalization and activation of signaling, both the IL-6R and gp130 are recycled back to the cell surface, a process that is enhanced by IL-6. These data reveal an important function of IL-6 beyond the pure activation of signaling.
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http://dx.doi.org/10.1016/j.jbc.2021.100434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010714PMC
August 2021

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Proc Natl Acad Sci U S A 2021 02;118(8)

Division of Medical Genetics, Health Sciences, Department of Biomedical Informatics, University of California San Diego, La Jolla, CA 92093.

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8 CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
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http://dx.doi.org/10.1073/pnas.2025840118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923353PMC
February 2021

Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2.

J Pathol 2021 May 18;254(1):80-91. Epub 2021 Mar 18.

Department of Medicine III, University Hospital Aachen, Aachen, Germany.

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5643DOI Listing
May 2021

Primary extranodal natural Killer/T-cell lymphoma in a child in the colon: A case report.

Medicine (Baltimore) 2021 Jan;100(3):e24232

Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Rationale: Primary extranodal natural killer (NK)/T-cell lymphoma (ENKTL) rarely occurs in childhood and adolescence. To the best of our knowledge, ENKTL of childhood in the gastrointestinal (GI) tract has not been reported yet.

Patient Concerns: A 12-year-old Chinese boy complained of abdominal pain and persistent fever for 1 month.

Diagnosis: Grossly an ulcerated tumor with perforation was located at the proximal ascending colon, 5 cm × 4 cm × 1.5 cm in diameter. The tumor was poorly circumscribed, tan-white and solid. Histological evaluation revealed medium-sized atypical lymphoid cells with large areas of necrosis distributed throughout all layers of the colon. Small blood vessels with destroyed walls were surrounded by lymphoid cells. Immunohistochemistry (IHC) highlighted tumor cells as strongly positive for CD3, CD56, CD5, CD2, CD8, CD4, CD43, T-cell restricted intracellular antigen 1 (TIA-1) and granzyme B. The proliferation index, measured by Ki-67 expression was high with 60%. The In situ hybridization (ISH) for EBER was positive. TCR was negative. Therefore, the final diagnosis was ENKTL of childhood in the colon.

Interventions: The patient underwent right hemicolectomy and ileocolostomy.

Outcomes: We recommended further evaluation and treatment, but the patient and patient family rejected further treatment of his condition. The patient died within 1 month after being discharged from hospital as a result of his disease.

Lessons: ENKTL of childhood in the GI tract is extremely rare. Due to the non-specific clinical symptoms, it is easy it is easy not to think of this differential diagnosis at early stage. If patients have GI symptoms, ENKTL cannot easily be ignored. It is necessary to diagnose ENKTL of childhood in the GI tract by morphology and immunohistochemistry, and to differentiate from the GI T-cell lymphomas. We hope this case may serve as a reference improving clinical diagnosis and treatment.
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http://dx.doi.org/10.1097/MD.0000000000024232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837927PMC
January 2021

Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma.

Cells 2021 02 2;10(2). Epub 2021 Feb 2.

Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Children suffering from high-risk and/or metastatic NB often show no response to therapy, and new therapeutic approaches are urgently needed. Malignant tumor development has been shown to be driven by the dysregulation of eukaryotic initiation factors (eIFs) at the translation initiation. Especially the activity of the heterotrimeric eIF4F complex is often altered in malignant cells, since it is the direct connection to key oncogenic signaling pathways such as the PI3K/AKT/mTOR-pathway. A large body of literature exists that demonstrates targeting the translational machinery as a promising anti-neoplastic approach. The objective of this study was to determine whether eIF4F complex members are aberrantly expressed in NB and whether targeting parts of the complex may be a therapeutic strategy against NB. We show that eIF4AI is overexpressed in NB patient tissue using immunohistochemistry, immunoblotting, and RT-qPCR. NB cell lines exhibit decreased viability, increased apoptosis rates as well as changes in cell cycle distribution when treated with the synthetic rocaglate CR-1-31-B, which clamps eIF4A and eIF4F onto mRNA, resulting in a translational block. Additionally, this study reveals that CR-1-31-B is effective against NB cell lines at low nanomolar doses (≤20 nM), which have been shown to not affect non-malignant cells in previous studies. Thus, our study provides information of the expression status on eIF4AI in NB and offers initial promising insight into targeting translation initiation as an anti-tumorigenic approach for NB.
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http://dx.doi.org/10.3390/cells10020301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912938PMC
February 2021

The Application of Fine Needle Aspiration Biopsy in the Diagnosis of Axillary Masses.

Acta Cytol 2021 3;65(3):213-219. Epub 2021 Feb 3.

Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China,

Introduction: We intend to determine the diagnostic power of fine needle aspiration biopsy (FNAB) for differentiation between malignant and benign lesions on axillary masses and draw the physicians' attention to the benefits of FNAB cytology in the diagnosis of axillary masses.

Methods: In this study, 1,328 patients with an axillary mass diagnosed by FNAB were retrospectively reviewed. These cases were registered at the affiliated hospital of Southwest Medical University (China), July 2014 to June 2017. Cytological results were verified either by histopathology following surgical resection or clinical follow-up.

Results: Of the 1,328 patients affected by axillary masses, 987 (74.3%) cases were female, and 341 (25.7%) cases were male. The highest incidence of patients was in the age group of 41-50 years (375, 28.2%). There were 1,129 (85.0%) patients with benign lesions and 199 (15.0%) with malignant lesions. Of the 199 malignant lesions cases, 21 cases were lymphomas, 2 cases were accessory breast cancers, and 176 cases were lymph node metastatic tumors. Under lymph node metastases, the most frequent primary tumors were breast cancer (141, 80.1%), followed by lung cancer (21, 11.9%). According to the study, the characters of 1,328 cases showed statistically significant difference (χ2 = 4.534, p = 0.033), and the incidence of females with axillary mass was significantly higher than that of males. There was a statistically significant difference in the distribution of benign and malignant cases in the patient age groups (χ2 = 1.129, p = 0.000), and the incidence of patients of 41-50 years of age was significantly higher than that of other patients. The diagnostic accuracy of FNAB in axillary masses was analyzed with the results of 95.98% of sensitivity, 99.56% of specificity, 97.45% of positive predictive value, and 99.29% of negative predictive value.

Conclusion: Our results confirm that FNAB is a valuable initial screening method regarding pathologic diagnosis of axillary mass, in particular with respect to malignancy in 41- to 50-year-old female patients.
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http://dx.doi.org/10.1159/000513149DOI Listing
June 2021

Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy.

Nat Commun 2021 01 5;12(1):117. Epub 2021 Jan 5.

Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.
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http://dx.doi.org/10.1038/s41467-020-20308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785735PMC
January 2021

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress.

Cancers (Basel) 2020 Oct 14;12(10). Epub 2020 Oct 14.

Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.

Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of and gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
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http://dx.doi.org/10.3390/cancers12102972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602170PMC
October 2020

Commentary: Discriminating α-synuclein strains in parkinson's disease and multiple system atrophy.

Front Neurosci 2020 25;14:802. Epub 2020 Aug 25.

Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.3389/fnins.2020.00802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477319PMC
August 2020

Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury.

Hepatology 2021 May 26;73(5):1836-1854. Epub 2021 Mar 26.

Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Background And Aims: Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC), the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Common bile duct ligation (BDL) is a well-established murine model to mimic cholestatic liver injury. Here, we hypothesized that pyroptotic cell death by the Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3 (Nlrp3) inflammasome plays an essential role during human and murine cholestasis.

Approach And Results: NLRP3 activation was analyzed in humans with cholestatic liver injury. Wild-type (WT) and Nlrp3 mice were subjected to BDL for 2 or 28 days. Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3-deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout, mice 28 days after BDL. In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, administration of MCC950, an NLRP3 small molecule inhibitor, reduced BDL-induced disease progression in WT mice.

Conclusions: NLRP3 activation correlates with disease activity in patients with PBC. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted through small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
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http://dx.doi.org/10.1002/hep.31494DOI Listing
May 2021

The Interplay of Tumor Stroma and Translational Factors in Endometrial Cancer.

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Area 2 Cancer, Center for Biomarker Research in Medicine, 8010 Graz, Austria.

Endometrial cancer (EC) is a common gynecologic malignancy which continues to have a poor prognosis in advanced stages due to current therapeutic limitations. A significant mechanism of chemoresistance in EC has been shown to also be the enhancement of epithelial to mesenchymal transition (EMT) and the subsequent obtainment of stem cell-like characteristics of EC. Current evidence on EMT in EC however fails to explain the relationship leading to an EMT signaling enhancement. Our review therefore focuses on understanding eukaryotic translation initiation factors (eIFs) as key regulators of the translational process in enhancing EMT and subsequently impacting higher chemoresistance of EC. We identified pathways connected to the development of a microenvironment for EMT, inducers of the process specifically related to estrogen receptors as well as their interplay with eIFs. In the future, investigation elucidating the translational biology of EC in EMT may therefore focus on the signaling between protein kinase RNA-like ER kinase (PERK) and eIF2alpha as well as eIF3B.
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http://dx.doi.org/10.3390/cancers12082074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463731PMC
July 2020
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