Publications by authors named "Thomas Mohr"

75 Publications

Systematic Analysis of the Transcriptome Profiles and Co-Expression Networks of Tumour Endothelial Cells Identifies Several Tumour-Associated Modules and Potential Therapeutic Targets in Hepatocellular Carcinoma.

Cancers (Basel) 2021 Apr 7;13(8). Epub 2021 Apr 7.

Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, A-1090 Vienna, Austria.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death, with tumour associated liver endothelial cells being thought to be major drivers in HCC progression. This study aims to compare the gene expression profiles of tumour endothelial cells from the liver with endothelial cells from non-tumour liver tissue, to identify perturbed biologic functions, co-expression modules, and potentially drugable hub genes that could give rise to novel therapeutic targets and strategies. Gene Set Variation Analysis (GSVA) showed that cell growth-related pathways were upregulated, whereas apoptosis induction, immune and inflammatory-related pathways were downregulated in tumour endothelial cells. Weighted Gene Co-expression Network Analysis (WGCNA) identified several modules strongly associated to tumour endothelial cells or angiogenic activated endothelial cells with high endoglin () expression. In tumour cells, upregulated modules were associated with cell growth, cell proliferation, and DNA-replication, whereas downregulated modules were involved in immune functions, particularly complement activation. In cells, upregulated modules were associated with cell adhesion and endothelial functions. One downregulated module was associated with immune system-related functions. Querying the database revealed known functional-interaction networks underlying the modules. Several possible hub genes were identified, of which some (for example , , , , and ) are potentially druggable as determined by querying the . In summary, our study provides a detailed picture of the transcriptomic differences between tumour and non-tumour endothelium in the liver on a co-expression network level, indicates several potential therapeutic targets and presents an analysis workflow that can be easily adapted to other projects.
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http://dx.doi.org/10.3390/cancers13081768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067977PMC
April 2021

ABO blood types and sepsis mortality.

Ann Intensive Care 2021 Apr 20;11(1):61. Epub 2021 Apr 20.

CHIP / PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, The Capital Region of Denmark, Denmark.

Background: We aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis. We also estimated the incidence of AKI and degree of endothelial damage, as measured by blood concentrations of soluble thrombomodulin and syndecan-1.

Results: We included 12,342 patients with severe sepsis. In a pooled analysis blood type B carried a slightly lower risk of 30-day all-cause mortality compared to non-blood type B (adjusted HR 0.88; 95%-CI 0.79-0.98; p = 0.02). There was no difference in the risk of AKI. Soluble thrombomodulin and syndecan-1 concentrations were lower in patients with blood type B and O compared to blood type A, suggesting less endothelial damage.

Conclusion: Septic patients with blood type B had less endothelial damage, and a small reduction in mortality. The exposure is, however, unmodifiable.
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http://dx.doi.org/10.1186/s13613-021-00844-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056100PMC
April 2021

EGF Induces Migration Independent of EMT or Invasion in A549 Lung Adenocarcinoma Cells.

Front Cell Dev Biol 2021 12;9:634371. Epub 2021 Mar 12.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Tumors and the tumor microenvironment produce multiple growth factors that influence cancer cell behavior via various signal transduction pathways. Growth factors, like transforming growth factor β (TGFβ) and epidermal growth factor (EGF), have been shown to induce proliferation, migration, and invasion in different cell models. Both factors are frequently overexpressed in cancer and will often act in combination. Although both factors are being used as rational targets in clinical oncology, the similarities and differences of their contributions to cancer cell migration and invasion are not fully understood. Here we compared the impact of treating A549 lung adenocarcinoma cells with TGFβ, EGF, and both in combination by applying videomicroscopy, functional assays, immunoblotting, real-time PCR, and proteomics. Treatment with both factors stimulated A549 migration to a similar extent, but with different kinetics. The combination had an additive effect. EGF-induced migration depended on activation of the mitogen-activated protein kinase (MAPK) pathway. However, this pathway was dispensable for TGFβ-induced migration, despite a strong activation of this pathway by TGFβ. Proteome analysis (data are available via ProteomeXchange with identifier PXD023024) revealed an overlap in expression patterns of migration-related proteins and associated gene ontology (GO) terms by TGFβ and EGF. Further, only TGFβ induced the expression of epithelial to mesenchymal transition (EMT)-related proteins like matrix metalloproteinase 2 (MMP2). EGF, in contrast, made no major contribution to EMT marker expression on either the protein or the transcript level. In line with these expression patterns, TGFβ treatment significantly increased the invasive capacity of A549 cells, while EGF treatment did not. Moreover, the addition of EGF failed to enhance TGFβ-induced invasion. Overall, these data suggest that TGFβ and EGF can partly compensate for each other for stimulation of cell migration, but abrogation of TGFβ signaling may be more suitable to suppress cell invasion.
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http://dx.doi.org/10.3389/fcell.2021.634371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994520PMC
March 2021

Prognostic factors of 90-day mortality in patients hospitalised with COVID-19.

Dan Med J 2021 Feb 22;68(3). Epub 2021 Feb 22.

Introduction: Mortality due to COVID-19 is higher among elderly patients with comorbidities. Even so, prognostication in COVID-19 remains limited.

Methods: We assessed 90-day mortality stratified by comorbidities, routine biochemical markers and oxygen need in a consecutive single-centre cohort from 2 March to 2 June 2020.

Results: We included 263 hospitalised patients with laboratory-confirmed COVID-19. On admission, fitness for intensive care was determined in 254 patients including 98 (39%) with a do-not-resuscitate order. Ninety-day overall mortality was 29%, whereas intensive care unit (ICU) mortality was 35% (14/40). Alcohol abuse, liver disease and elevated urea were strongly associated with mortality in univariable analyses. In a mutually adjusted multivariable analysis, we found an independent incremental increase in 90-day mortality with each increasing age by decade (hazard ratio (HR) = 1.5; 95% confidence interval (CI): 1.2-1.9), Charlson Comorbidity Index (CCI) score (HR = 1.2; 95% CI: 1.0-1.4), number of abnormal blood tests (HR = 1.2; 95% CI: 1.1-1.3) and l/min. of supplemental oxygen (HR = 1.1; 95% CI: 1.1-1.2).

Conclusions: The overall mortality was similar to that of other hospitalised patients, whereas the ICU mortality was lower than expected. On admission, each additional age by decade, CCI score, number of abnormal blood tests and magnitude of supplemental oxygen were independently associated with increased mortality.

Funding: none.

Trial Registration: not relevant.
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February 2021

Cardiac arrhythmias in critically ill patients with coronavirus disease 2019: A retrospective population-based cohort study.

Acta Anaesthesiol Scand 2021 Feb 27. Epub 2021 Feb 27.

Department of Intensive Care, Rigshospitalet University of Copenhagen, Copenhagen, Denmark.

Background: Coronavirus disease 2019 (COVID-19) may be associated with cardiac arrhythmias in hospitalized patients, but data from the ICU setting are limited. We aimed to describe the epidemiology of cardiac arrhythmias in ICU patients with COVID-19.

Methods: We conducted a multicenter, retrospective cohort study including all ICU patients with an airway sample positive for severe acute respiratory syndrome corona-virus 2 from March 1st to June 1st in the Capital Region of Denmark (1.8 million inhabitants). We registered cardiac arrhythmias in ICU, potential risk factors, interventions used in ICU and outcomes.

Results: From the seven ICUs we included 155 patients with COVID-19. The incidence of cardiac arrhythmias in the ICU was 57/155 (37%, 95% confidence interval 30-45), and 39/57 (68%) of these patients had this as new-onset arrhythmia. Previous history of tachyarrhythmias and higher disease severity at ICU admission were associated with cardiac arrhythmias in the adjusted analysis. Fifty-four of the 57 (95%) patients had supraventricular origin of the arrhythmia, 39/57 (68%) received at least one intervention against arrhythmia (eg amiodarone, IV fluid or magnesium) and 38/57 (67%) had recurrent episodes of arrhythmia in ICU. Patients with arrhythmias in ICU had higher 60-day mortality (63%) as compared to those without arrhythmias (39%).

Conclusion: New-onset supraventricular arrhythmias were frequent in ICU patients with COVID-19 and were related to previous history of tachyarrhythmias and severity of the acute disease. The mortality was high in these patients despite the frequent use of interventions against arrhythmias.
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http://dx.doi.org/10.1111/aas.13806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014528PMC
February 2021

Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype.

Med Oncol 2021 Feb 11;38(3):24. Epub 2021 Feb 11.

Medical Oncology, Department of Precision Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Napoli, Campania, Italy.

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease.
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http://dx.doi.org/10.1007/s12032-021-01464-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878213PMC
February 2021

Joining European Scientific Forces to Face Pandemics.

Trends Microbiol 2021 02 4;29(2):92-97. Epub 2020 Dec 4.

Department of Oncology, University of Turin, IT-10126, Turin, Italy. Electronic address:

Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration.
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http://dx.doi.org/10.1016/j.tim.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716745PMC
February 2021

Hybrid Approaches for Selective Laser Sintering by Building on Dissimilar Materials.

Materials (Basel) 2020 Nov 22;13(22). Epub 2020 Nov 22.

Applied Laser and Photonics Group, University of Applied Sciences Aschaffenburg, Wuerzburger Str. 45, 63743 Aschaffenburg, Germany.

We introduced a new approach in selective laser sintering for hybrid multicomponent systems by fabricating the sintered polyamide 12 (PA12) part directly onto a similar (PA12) or dissimilar (polyamide 6 (PA6) and tool steel 1.2709) joining partner. Thus, the need for adhesive substances or joining pressure was completely circumvented, leading to the possibility of pure hybrid lightweight bi-polymer or metal-polymer systems. By taking advantage of the heating capabilities of the sinter laser regarding the substrate surface, different exposure strategies circumvented the lack of overlapping melting temperatures of dissimilar polymers. Therefore, even sintering on non-PA12 polymers was made possible. Finally, the transfer on metallic substrates-made up by selective laser melting (SLM)-was successfully performed, closing the gap between two powder-based additive processes, selective laser sintering (SLS) and SLM.
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http://dx.doi.org/10.3390/ma13225285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700680PMC
November 2020

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

Acta Anaesthesiol Scand 2021 01 3;65(1):68-75. Epub 2020 Oct 3.

Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark.

Background: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded.

Methods: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis.

Results: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities.

Conclusions: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.
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http://dx.doi.org/10.1111/aas.13701DOI Listing
January 2021

Preferences of Physical Therapy Students Regarding Digital and Printed Textbooks.

J Allied Health 2020 ;49(3):169-175

Dep. of Physical Therapy, Univ. of North Dakota School of Medicine and Health Sciences, 1301 N. Columbia Rd., Stop 9037, Grand Forks, ND 58202, USA. Tel 701-777-3862, fax 701-777-4199.

Aims: Research has shown mixed results regarding students' preferences of digital over printed textbooks. However, none of the published studies have studied physical therapy students and few have surveyed students across more than one professional program. The purpose of this study was to identify the perceptions and use of digital textbooks and printed textbooks by students in four different physical therapy programs.

Methods: We surveyed first-, second-, and third-year physical therapist students from four physical therapy programs in different regions of the United States. Descriptive statistics were used to report the students' responses. Chi square tests of independence were used for all comparisons between genders and years in the program with a=0.05.

Results: More students had purchased or leased printed textbooks than digital textbooks. Students preferred digital textbooks for portability, cost, and search ability. Students preferred printed textbooks for studying and preparing for examinations. Printed textbooks were preferred for readability, comprehension, retention, and studying and were less tiring on the eyes. Males preferred digital textbooks and females preferred printed textbooks. Students in Years 2 and 3 of the programs preferred digital textbooks, and students in Year 1 preferred printed textbooks for some features.

Conclusion: Students preferred digital textbooks for convenience factors and printed textbooks for learning.
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January 2020

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

Acta Anaesthesiol Scand 2020 10 30;64(9):1365-1375. Epub 2020 Jul 30.

Department of Anaesthesia and Intensive Care, Odense University Hospital, Odense, Denmark.

Introduction: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.
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http://dx.doi.org/10.1111/aas.13673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404666PMC
October 2020

IDO1 Paneth cells promote immune escape of colorectal cancer.

Commun Biol 2020 05 22;3(1):252. Epub 2020 May 22.

Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria.

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1) Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1 Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1 Paneth cells as a target for immunotherapy.
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http://dx.doi.org/10.1038/s42003-020-0989-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244549PMC
May 2020

Interaction of FGF9 with FGFR3-IIIb/IIIc, a putative driver of growth and aggressive behaviour of hepatocellular carcinoma.

Liver Int 2020 09 17;40(9):2279-2290. Epub 2020 Jun 17.

Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

Background & Aims: Recently, overexpression of the fibroblast growth factor receptor 3 (FGFR3) splice variants FGFR3-IIIb and FGFR3-IIIc was found in ~50% of hepatocellular carcinoma (HCC). Here, we aim to identify FGFR3-IIIb/IIIc ligands, which drive the progression of HCC.

Methods: FACS, MTT assay and/or growth curves served to identify the FGFR3-IIIb/IIIc ligand being most effective to induce growth of hepatoma/hepatocarcinoma cell lines, established from human HCC. The most potent FGF was characterized regarding the expression levels in epithelial and stromal cells of liver and HCC and impact on neoangiogenesis, clonogenicity and invasive growth of hepatoma/hepatocarcinoma cells.

Results: Among all FGFR3-IIIb/IIIc ligands tested, FGF9 was the most potent growth factor for hepatoma/hepatocarcinoma cells. Replication and/or sprouting of blood/lymphendothelial cells was stimulated as well. FGF9 occurred mainly in stromal cells of unaltered liver but in epithelial cells of HCC. Every fifth HCC exhibited overexpressed FGF9 and frequent co-upregulation of FGFR3-IIIb/IIIc. In hepatoma/hepatocarcinoma cells FGF9 enhanced the capability for clonogenicity and disintegration of the blood and lymphatic endothelium, being most pronounced in cells overexpressing FGFR3-IIIb or FGFR3-IIIc, respectively. Any of the FGF9 effects in hepatoma/hepatocarcinoma cells was blocked completely by applying the FGFR1-3-specific tyrosine kinase inhibitor BGJ398 or siFGFR3, while siFGFR1/2/4 were mostly ineffective.

Conclusions: FGF9 acts via FGFR3-IIIb/IIIc to enhance growth and aggressiveness of HCC cells. Accordingly, blockade of the FGF9-FGFR3-IIIb/IIIc axis may be an efficient therapeutic option for HCC patients.
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http://dx.doi.org/10.1111/liv.14505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496895PMC
September 2020

STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer.

Mol Syst Biol 2020 04;16(4):e9247

Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
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http://dx.doi.org/10.15252/msb.20199247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178451PMC
April 2020

Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Clin Cancer Res 2020 07 21;26(14):3819-3830. Epub 2020 Apr 21.

Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Purpose: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase () gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.

Experimental Design: promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for immortalization. The respective MPM cell models ( = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.

Results: promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines promoter mutations were associated with enforced promoter activity and mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While mutations/deletions were exclusive with promoter mutations, homozygous deletions at the and the loci were clearly enriched in mutated cases.

Conclusions: promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3573DOI Listing
July 2020

Lipid droplet-mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib.

Int J Cancer 2020 09 2;147(6):1680-1693. Epub 2020 Mar 2.

Department of Medicine I, Medical University of Vienna, Institute of Cancer Research and Comprehensive Cancer Center, Vienna, Austria.

Ponatinib is a small molecule multi-tyrosine kinase inhibitor clinically approved for anticancer therapy. Molecular mechanisms by which cancer cells develop resistance against ponatinib are currently poorly understood. Likewise, intracellular drug dynamics, as well as potential microenvironmental factors affecting the activity of this compound are unknown. Cell/molecular biological and analytical chemistry methods were applied to investigate uptake kinetics/subcellular distribution, the role of lipid droplets (LDs) and lipoid microenvironment compartments in responsiveness of FGFR1-driven lung cancer cells toward ponatinib. Selection of lung cancer cells for acquired ponatinib resistance resulted in elevated intracellular lipid levels. Uncovering intrinsic ponatinib fluorescence enabled dissection of drug uptake/retention kinetics in vitro as well as in mouse tissue cryosections, and revealed selective drug accumulation in LDs of cancer cells. Pharmacological LD upmodulation or downmodulation indicated that the extent of LD formation and consequent ponatinib incorporation negatively correlated with anticancer drug efficacy. Co-culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib-selected cancer cells exhibited increased LD levels and enhanced ponatinib deposition into this organelle. Our findings demonstrate intracellular deposition of the clinically approved anticancer compound ponatinib into LDs. Furthermore, increased LD biogenesis was identified as adaptive cancer cell-defense mechanism via direct drug scavenging. Together, this suggests that LDs represent an underestimated organelle influencing intracellular pharmacokinetics and activity of anticancer tyrosine kinase inhibitors. Targeting LD integrity might constitute a strategy to enhance the activity not only of ponatinib, but also other clinically approved, lipophilic anticancer therapeutics.
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http://dx.doi.org/10.1002/ijc.32924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497038PMC
September 2020

Hair eruption initiates and commensal skin microbiota aggravate adverse events of anti-EGFR therapy.

Sci Transl Med 2019 12;11(522)

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna and Comprehensive Cancer Center, Vienna 1090, Austria.

Epidermal growth factor receptor (EGFR)-targeted anticancer therapy induces stigmatizing skin toxicities affecting patients' quality of life and therapy adherence. The lack of mechanistic details underlying these adverse events hampers their management. We found that EGFR/ERK signaling is required in LRIG1-positive stem cells during de novo hair eruption to secure barrier integrity and prevent the invasion of commensal microbiota and inflammatory skin disease. EGFR-deficient epidermis is permissive for microbiota outgrowth and displays an atopic-like T2-dominated signature. The opening of the follicular ostia during hair eruption allows invasion of commensal microbiota into the hair follicle, initiating an additional T1 and T17 response culminating in chronic folliculitis. Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression rescues the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point. These data reveal that commensal skin microbiota provoke atopic-like inflammatory skin diseases by invading into the follicular opening of erupting hair.
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http://dx.doi.org/10.1126/scitranslmed.aax2693DOI Listing
December 2019

Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas.

Cells 2019 09 16;8(9). Epub 2019 Sep 16.

Department of Surgery, Medical University of Vienna and Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Spitalgasse 23, 1090 Vienna, Austria.

Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients' survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies.
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http://dx.doi.org/10.3390/cells8091092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770911PMC
September 2019

Proteomic identification of a marker signature for MAPKi resistance in melanoma.

EMBO J 2019 08 26;38(15):e95874. Epub 2019 Jun 26.

Department of Dermatology, University of Zurich Hospital, University of Zurich, Zurich, Switzerland.

MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. The ability of melanoma cells to switch from melanocytic to mesenchymal phenotypes appears to be associated with therapeutic resistance. High-throughput, subcellular proteome analyses and RNAseq on two panels of primary melanoma cells that were either sensitive or resistant to MAPKi revealed that only 15 proteins were sufficient to distinguish between these phenotypes. The two proteins with the highest discriminatory power were PTRF and IGFBP7, which were both highly upregulated in the mesenchymal-resistant cells. Proteomic analysis of CRISPR/Cas-derived PTRF knockouts revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFβ signalling and cell migration and adhesion, as well as a significantly reduced invasive index and ability to form spheres in 3D culture. Overexpression of PTRF led to MAPKi resistance, increased cell adhesion and sphere formation. In addition, immunohistochemistry of patient samples showed that PTRF expression levels were a significant biomarker of poor progression-free survival, and IGFBP7 levels in patient sera were shown to be higher after relapse.
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http://dx.doi.org/10.15252/embj.201695874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669927PMC
August 2019

Biomarker-assisted identification of sepsis-related acute liver impairment: a frequent and deadly condition in critically ill patients.

Clin Chem Lab Med 2019 08;57(9):1422-1431

CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark.

Background The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. Methods A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson's co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. Results HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2-556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9-116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9-1.8], p = 0.14, 3rd quartile: 1.5 [1.1-2.2], p = 0.02, 4th quartile: 1.9 [1.3-2.6], p < 0.0001). High bilirubin was also an independent predictor of mortality. Conclusions Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.
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http://dx.doi.org/10.1515/cclm-2018-1350DOI Listing
August 2019

EGFR is required for FOS-dependent bone tumor development via RSK2/CREB signaling.

EMBO Mol Med 2018 11;10(11)

Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c-Fos-dependent OS mouse model (H2LTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti-EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2-LTR mice by directly inhibiting the proliferation of cancer-initiating osteoblastic cells by a mechanism involving RSK2/CREB-dependent c-Fos expression. Furthermore, OS patients with co-expression of EGFR and c-Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c-Fos responded to anti-EGFR therapy demonstrating that c-Fos can be considered as a novel biomarker predicting response to anti-EGFR treatment in OS patients.
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http://dx.doi.org/10.15252/emmm.201809408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220323PMC
November 2018

The thiosemicarbazone MeNNMe induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition.

Cell Death Dis 2018 10 15;9(11):1052. Epub 2018 Oct 15.

Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative MeNNMe differs from Triapine not only in its efficacy but also in its mode of action. Here we show that MeNNMe- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of MeNNMe (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca and ER thiol redox homeostasis. Our findings indicate that compounds like MeNNMe are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.
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http://dx.doi.org/10.1038/s41419-018-1102-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189190PMC
October 2018

Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins.

Oncotarget 2018 May 22;9(39):25661-25680. Epub 2018 May 22.

Institute of Cancer Research, Department of Internal Medicine I, Medical University of Vienna, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.

Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have established destruxin-resistant sublines of HCT116 colon carcinoma cells by selection with the most prevalent derivatives, destruxin (dtx)A, dtxB and dtxE. Various cell biological and molecular techniques were applied to elucidate the regulatory mechanisms underlying these acquired and highly stable destruxin resistance phenotypes. Interestingly, well-known chemoresistance-mediating ABC efflux transporters were not the major players. Instead, in dtxA- and dtxB-resistant cells a hyper-activated mevalonate pathway was uncovered resulting in increased cholesterol synthesis rates and elevated levels of lanosterol, cholesterol as well as several oxysterol metabolites. Accordingly, inhibition of the mevalonate pathway at two different steps, using either statins or zoledronic acid, significantly reduced acquired but also intrinsic destruxin resistance. Vice versa, cholesterol supplementation protected destruxin-sensitive cells against their cytotoxic activity. Additionally, an increased cell membrane adhesiveness of dtxA-resistant as compared to parental cells was detected by atomic force microscopy. This was paralleled by a dramatically reduced ionophoric capacity of dtxA in resistant cells when cultured in absence but not in presence of statins. Summarizing, our results suggest a reduced ionophoric activity of destruxins due to cholesterol-mediated plasma membrane re-organization as molecular mechanism underlying acquired destruxin resistance in human colon cancer cells. Whether this mechanism might be valid also in other cell types and organisms exposed to destruxins e.g. as bio-insecticides needs to be evaluated.
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http://dx.doi.org/10.18632/oncotarget.25432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986646PMC
May 2018

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal.

Carcinogenesis 2018 04;39(4):534-545

Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna.

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
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http://dx.doi.org/10.1093/carcin/bgy018DOI Listing
April 2018

STAT1 is a sex-specific tumor suppressor in colitis-associated colorectal cancer.

Mol Oncol 2018 04 20;12(4):514-528. Epub 2018 Feb 20.

Institute of Cancer Research, Medical University Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.

The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1 ). Male but not female STAT1 mice were more resistant to DSS-induced colitis than sex-matched STAT1 controls and displayed reduced intraepithelial infiltration of CD8 TCRαβ granzyme B T cells. Moreover, DSS treatment failed to induce expression of T-cell-attracting chemokines in intestinal epithelial cells of male but not of female STAT1 mice. Application of the AOM-DSS protocol for induction of colitis-associated CRC resulted in increased intestinal tumor load in male but not in female STAT1 mice. A sex-specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell-intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women. These data demonstrate that epithelial STAT1 is a male-specific tumor suppressor in CRC of mice and humans.
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http://dx.doi.org/10.1002/1878-0261.12178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891040PMC
April 2018

Serum proteomic pattern in female stress urinary incontinence.

Electrophoresis 2018 04 6;39(8):1071-1078. Epub 2018 Feb 6.

Core Facility Proteomics, Clinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

The pathophysiology of Stress Urinary Incontinence (SUI) is poorly understood. The aim of this study was to identify the serum proteomic profile in patients with SUI and to replicate findings from a preceding study in which a significant difference in the urinary proteome was identified. Serum samples were collected from 38 patients (19 SUI; 19 matched, continent controls). Sample preparation included serum albumin depletion, in-solution enzymatic digestion of proteins applying a combination of Gluc-C and trypsin and peptide separation using nano High Performance Liquid Chromatography. Label-free quantitation of peptides and proteins was performed after triplicate measurements using quadrupole time-of-flight mass spectrometry. Peptide identification was achieved by searching the Human SwissProt Database using Mascot and X!Tandem. Main outcome measure was the relative abundance of each detected protein in serum. Of 7012 identified proteins, 33 proteins were induced (detected in SUI, not in controls) and five proteins were depleted (detected in controls, not in SUI). All depleted proteins play a role in immune/DNA damage response. Induced proteins are involved in inflammatory response, response to cellular stress, coagulation and cytoskeleton stability/ motility. Plasma serine protease inhibitor (SERPINA5) was found induced and previously also showed a higher abundance in urine samples of SUI patients. Data are available via ProteomeXchange with identifier PXD008553.
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http://dx.doi.org/10.1002/elps.201700423DOI Listing
April 2018

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

Lancet Respir Med 2018 03 8;6(3):183-192. Epub 2018 Jan 8.

Centre of Excellence in Immunity and Infection/Centre of Excellence for Personalised Medicine of Infectious Complications in Immune Deficiency, Department of Infectious Diseases, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark; Respiratory Medicine Division, Department of Internal Medicine, Herlev and Gentofte Hospital, Hellerup, Denmark. Electronic address:

Background: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.

Methods: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116.

Findings: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]).

Interpretation: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock.

Funding: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.
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http://dx.doi.org/10.1016/S2213-2600(18)30004-3DOI Listing
March 2018

Organotypic three-dimensional cancer cell cultures mirror drug responses : lessons learned from the inhibition of EGFR signaling.

Oncotarget 2017 Dec 17;8(64):107423-107440. Epub 2017 Nov 17.

IMC University of Applied Sciences Krems, Department Life Sciences, Research Institute for Applied Bioanalytics and Drug Development, A-3500 Krems, Austria.

Complex three-dimensional (3D) models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments.
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http://dx.doi.org/10.18632/oncotarget.22475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746077PMC
December 2017

Proteomic profiling identifies markers for inflammation-related tumor-fibroblast interaction.

Clin Proteomics 2017 6;14:33. Epub 2017 Oct 6.

Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Cancer associated fibroblasts are activated in the tumor microenvironment and contribute to tumor progression, angiogenesis, extracellular matrix remodeling, and inflammation.

Methods: To identify proteins characteristic for fibroblasts in colorectal cancer we used liquid chromatography-tandem mass spectrometry to derive protein abundance from whole-tissue homogenates of human colorectal cancer/normal mucosa pairs. Alterations of protein levels were determined by two-sided t test with greater than threefold difference and an FDR of < 0.05. Public available datasets were used to predict proteins of stromal origin and link protein with mRNA regulation. Immunohistochemistry confirmed the localization of selected proteins.

Results: We identified a set of 24 proteins associated with inflammation, matrix organization, TGFβ receptor signaling and angiogenesis mainly originating from the stroma. Most prominent were increased abundance of SerpinB5 in the parenchyme and latent transforming growth factor β-binding protein, thrombospondin-B2, and secreted protein acidic-and-cysteine-rich in the stroma. Extracellular matrix remodeling involved collagens type VIII, XII, XIV, and VI as well as lysyl-oxidase-2. In silico analysis of mRNA levels demonstrated altered expression in the tumor and the adjacent normal tissue as compared to mucosa of healthy individuals indicating that inflammatory activation affected the surrounding tissue. Immunohistochemistry of 26 tumor specimen confirmed upregulation of SerpinB5, thrombospondin B2 and secreted protein acidic-and-cysteine-rich.

Conclusions: This study demonstrates the feasibility of detecting tumor- and compartment-specific protein-signatures that are functionally meaningful by proteomic profiling of whole-tissue extracts together with mining of RNA expression datasets. The results provide the basis for further exploration of inflammation-related stromal markers in larger patient cohorts and experimental models.
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http://dx.doi.org/10.1186/s12014-017-9168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689177PMC
October 2017

FGF5 is expressed in melanoma and enhances malignancy and .

Oncotarget 2017 Oct 23;8(50):87750-87762. Epub 2017 Sep 23.

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

Although FGF5 mRNA was previously found expressed in some melanoma cell lines in contrast to normal human melanocytes, neither its contribution to melanoma growth nor its expression in melanoma tissue has been investigated. Here we demonstrate that ectopic overexpression of FGF5 in human melanoma cells with low endogenous FGF5 expression increased clonogenicity and invasion but not short-term growth . Silencing of FGF5 in melanoma cells with high endogenous FGF5 expression had the opposite effect on clonogenicity. FGF overexpression led to increased signaling along the MAPK and NFAT axis but had no effect on STAT3 signaling. In an experiment in immunocompromised mice, human melanoma xenografts overexpressing FGF5 showed enhanced tumor growth, a higher Ki-67 proliferation index, decreased apoptosis and enhanced angiogenesis. Immunohistochemistry performed on a tissue microarray demonstrated FGF5 protein expression in more than 50% of samples of melanoma and benign nevi. These data suggest that FGF5 has oncogenic potential in melanoma cells and contributes to melanoma growth in a subset of patients. This highlights the importance of further evaluating FGF5 as potential biomarker and therapy target in melanoma.
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http://dx.doi.org/10.18632/oncotarget.21184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675669PMC
October 2017