Publications by authors named "Hubert Hackl"

107 Publications

Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer.

Oncogene 2021 Apr 1. Epub 2021 Apr 1.

Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2 generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.
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http://dx.doi.org/10.1038/s41388-021-01754-0DOI Listing
April 2021

The Addition of C-Reactive Protein and von Willebrand Factor to MELD-Na Improves Prediction of Waitlist Mortality.

Hepatology 2021 Mar 31. Epub 2021 Mar 31.

Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA.

Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed due to complications of portal hypertension (PH) or infections. Von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. We determined whether addition of vWF-Ag and CRP to the MELD-Na score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in 2 independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (N=269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na: 0.764, MELD-Na+CRP: 0.790, MELD-Na+vWF: 0.803, MELD-Na+CRP+vWF-Ag: 0.824). Results were confirmed in an independent validation cohort (N=129, AUC: MELD-Na: 0.677, MELD-Na+CRP+vWF-Ag: 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, while CRP closely, and MELD-independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSION: The addition of vWF-Ag and CRP - reflecting central pathophysiological mechanisms of PH, bacterial translocation and inflammation, that are all drivers of mortality on the waiting list for LT - to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.
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http://dx.doi.org/10.1002/hep.31838DOI Listing
March 2021

Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness.

Leukemia 2021 Mar 29. Epub 2021 Mar 29.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.
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http://dx.doi.org/10.1038/s41375-021-01224-2DOI Listing
March 2021

Noninvasive evaluation of intragraft immune responses in upper extremity transplantation.

Transpl Int 2021 Feb 24. Epub 2021 Feb 24.

Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

In vascularized composite allotransplantation (VCA), invasive tissue biopsies remain the gold standard in diagnosing rejection carrying significant morbidity. We aimed to show feasibility of tape-stripping for noninvasive immune monitoring in VCA. Tape-stripping was performed on allografts and native skin of upper extremity transplant recipients. Healthy nontransplanted individuals served as controls. The technique was also used in swine on naïve skin in nontransplanted animals, native skin of treated, transplanted swine, nonrejecting VCAs, and rejecting VCAs. Extracted protein was analyzed for differences in cytokine expression using Luminex technology. Significantly decreased levels of INFγ and IL-1Ra were seen between human allograft samples and native skin. In swine, rejecting grafts had increased IL-1Ra compared to naïve and native skin, decreased levels of GM-CSF compared to native skin, and decreased IL-10 compared to nonrejecting grafts. Unsupervised hierarchical clustering revealed rejecting grafts separated from the nonrejecting (P = 0.021). Variable importance in projection scores identified GM-CSF, IL-1Ra, and IL-2 as the most important profiles for group discrimination. Differences in cytokine expression are detectable in human VCA patient native skin and VCA graft skin using a noninvasive tape-stripping method. Swine studies suggest that differences in cytokines between rejecting and nonrejecting grafts are discernable.
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http://dx.doi.org/10.1111/tri.13854DOI Listing
February 2021

Overcoming negative predictions of microRNA expressions to gemcitabine response with FOLFIRINOX in advanced pancreatic cancer patients.

Future Sci OA 2020 Nov 30;7(2):FSO644. Epub 2020 Nov 30.

IIIrd Medical Department with Hematology & Medical Oncology, Hemostaseology, Rheumatology & Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, Salzburg 5020, Austria.

FOLFIRINOX is superior to gemcitabine in patients with pancreatic cancer, but this regimen is associated with toxicity and biomarkers for response are warranted. MicroRNAs can mediate drug resistance and could provide predictive information. Altered expressions of several microRNAs including miR-21-5p, miR-10b-5p and miR-34a-5p have been previously linked to a worse response to gemcitabine. We investigated the influence of expression levels in tumor tissue of those three microRNAs on outcome to FOLFIRINOX. Twenty-nine patients with sufficient formalin-fixed paraffin-embedded tumor tissue were identified. There was no significant association between high and low expression groups for these three microRNA. We conclude that polychemotherapy combination can overcome intrinsic negative prognostic factors.
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http://dx.doi.org/10.2144/fsoa-2020-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787156PMC
November 2020

Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis.

Cancer Metab 2020 Nov 26;8(1):26. Epub 2020 Nov 26.

Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010, Graz, Austria.

Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.

Results: Low AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.

Conclusion: This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo.
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http://dx.doi.org/10.1186/s40170-020-00232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690131PMC
November 2020

Clinical impact of BRCA2 mRNA expression in high-grade serous ovarian cancer: validation using the TCGA cohort.

Acta Oncol 2021 Feb 4;60(2):187-190. Epub 2020 Nov 4.

Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1080/0284186X.2020.1841288DOI Listing
February 2021

Consequences of Perioperative Serotonin Reuptake Inhibitor Treatment During Hepatic Surgery.

Hepatology 2020 Oct 20. Epub 2020 Oct 20.

Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria.

Background And Aims: Platelet-stored serotonin critically affects liver regeneration in mice and humans. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs) reduce intraplatelet serotonin. As SSRIs/SNRIs are now one of the most commonly prescribed drugs in the United States and Europe and given serotonin's impact on liver regeneration, we evaluated whether perioperative use of SSRIs/SNRIs affects outcome after hepatic resection.

Approach And Results: Consecutive patients undergoing hepatic resection (n = 754) were retrospectively included from prospectively maintained databases from two European institutions. Further, an independent cohort of 495 patients from the United States was assessed to validate our exploratory findings. Perioperative intake of SSRIs/SNRIs was recorded, and patients were followed up for postoperative liver dysfunction (LD), morbidity, and mortality. Perioperative intraplatelet serotonin levels were significantly decreased in patients receiving SSRI/SNRI treatment. Patients treated with SSRIs/SNRIs showed a higher incidence of morbidity, severe morbidity, LD, and LD requiring intervention. Associations were confirmed in the independent validation cohort. Combined cohorts documented a significant increase in deleterious postoperative outcome (morbidity odds ratio [OR], 1.56; 95% confidence interval [CI], 1.07-2.31; severe morbidity OR, 1.86; 95% CI, 1.22-2.79; LD OR, 1.96; 95% CI, 1.23-3.06; LD requiring intervention OR, 2.22; 95% CI, 1.03-4.36). Further, multivariable analysis confirmed the independent association of SSRIs/SNRIs with postoperative LD, which was closely associated with postoperative 90-day mortality and 1-year overall survival.

Conclusions: We observed a significant association of perioperative SSRI/SNRI intake with adverse postoperative outcome after hepatic resection. This indicates that SSRIs/SNRIs should be avoided perioperatively in patients undergoing hepatic resections.
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http://dx.doi.org/10.1002/hep.31601DOI Listing
October 2020

Hospitalizations and Clinical Outcome in Metastatic Colorectal Cancer During Regorafenib or TAS-102 Therapy.

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria.

Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of hospitalizations on overall survival (OS). This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 at the tertiary cancer centers in Salzburg and Wels-Grieskirchen, Austria. Between January 2013 and May 2019, 93 patients started third- or fourth-line therapy with regorafenib or TAS-102. Tumor therapy (regorafenib versus TAS-102, HR: 1.95 [95% CI: 1.07-3.54], = 0.03) and the Eastern Cooperative Oncology Group (ECOG) performance status (2-3 versus 0-1, HR: 4.04 [95% CI: 2.11-7.71], < 0.001) showed a statistically significant association with hospitalization risk in multivariate analysis. The corresponding hospitalization probability from initiation of third- or fourth-line was 30% with regorafenib versus 18% with TAS-102 at five weeks and 41% versus 28% at ten weeks, respectively. Hospitalizations irrespective of cause during regorafenib or TAS-102 therapy did neither impact median survival in patients undergoing only third-line therapy (never-hospitalized: 5.7 months [95% CI: 3.9-10.5] versus hospitalized: 5.4 months [95% CI: 2.8-9.6], = 0.45), nor in patients receiving third- and fourth-line therapy (12.2 months [95% CI: 10.6-28.8] versus 18.6 months [95% CI: 6.3-not reached], = 0.90). In conclusion, apart from poor ECOG performance status, regorafenib therapy was associated with an increased hospitalization probability during palliative systemic third- and fourth-line therapy in mCRC. However, hospitalizations during regorafenib or TAS-102 therapy did not impact OS beyond second-line therapy.
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http://dx.doi.org/10.3390/cancers12102812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599669PMC
September 2020

Long-term outcome after hand and forearm transplantation - a retrospective study.

Transpl Int 2020 Dec 10;33(12):1762-1778. Epub 2020 Nov 10.

Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.

Between 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long-term results at 20 years. During the 6-20 years follow-up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody-related with serum donor-specific alloantibodies (DSA) and skin-infiltrating B-cells. The cell phenotype in rejecting skin biopsies changed and C4d-staining increased with time post-transplantation. In the long-term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well-being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection-free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.
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http://dx.doi.org/10.1111/tri.13752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756600PMC
December 2020

Shock waves promote spinal cord repair via TLR3.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Department of Cardiac Surgery and.

Spinal cord injury (SCI) remains a devastating condition with poor prognosis and very limited treatment options. Affected patients are severely restricted in their daily activities. Shock wave therapy (SWT) has shown potent regenerative properties in bone fractures, wounds, and ischemic myocardium via activation of the innate immune receptor TLR3. Here, we report on the efficacy of SWT for regeneration of SCI. SWT improved motor function and decreased lesion size in WT but not Tlr3-/- mice via inhibition of neuronal degeneration and IL6-dependent recruitment and differentiation of neuronal progenitor cells. Both SWT and TLR3 stimulation enhanced neuronal sprouting and improved neuronal survival, even in human spinal cord cultures. We identified tlr3 as crucial enhancer of spinal cord regeneration in zebrafish. Our findings indicate that TLR3 signaling is involved in neuroprotection and spinal cord repair and suggest that TLR3 stimulation via SWT could become a potent regenerative treatment option.
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http://dx.doi.org/10.1172/jci.insight.134552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455067PMC
August 2020

Initial Evidence of Distinguishable Bacterial and Fungal Dysbiosis in the Skin of Patients with Atopic Dermatitis or Netherton Syndrome.

J Invest Dermatol 2021 Jan 14;141(1):114-123. Epub 2020 Jun 14.

Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Atopic dermatitis (AD) is an inflammatory skin disease in which epidermal barrier impairment, often owing to FLG null mutations, precedes immune hyperresponsiveness. Ichthyosis vulgaris is characterized by FLG null mutations and noninflamed dry skin. Netherton syndrome (NS), caused by SPINK5 null mutations, is characterized by generalized erythroderma with scaling and atopic manifestations. The goal of this work was to evaluate associations between specific skin disease features, such as ichthyotic and/or atopic manifestations, and the skin bacterial and fungal microbiota. Taxon diversity showed greater variation in the bacterial microbiota than in the fungal microbiota in the skin diseases. The relative abundances of Firmicutes (Staphylococcus) and Actinobacteria (Corynebacterium) were augmented in ichthyosis vulgaris, AD, and NS, whereas those of Proteobacteria/Enhydrobacter and Bacteroidetes were reduced, regardless of body site. Furthermore, proportions of Staphylococcus were correlated with transepidermal water loss and serum IgE levels. Nevertheless, the skin of patients with low to mild AD was overcolonized with Staphylococcus epidermidis and not with Staphylococcus aureus. Ascomycota were increased in both AD and NS, but from expansion of different fungal species. Finally, the expansion of pathologic bacteria in AD and NS might be supported by surrounding fungi. Thus, distinguishable bacterial and fungal skin dysbiosis in AD, NS, and ichthyosis vulgaris emphasizes disease-specific pathomechanisms.
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http://dx.doi.org/10.1016/j.jid.2020.05.102DOI Listing
January 2021

Low Expression of miR-20a-5p Predicts Benefit to Bevacizumab in Metastatic Breast Cancer Patients Treated within the TANIA Phase III Trial.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute, Oncologic Center Salzburg, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

Background: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value.

Methods: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab.

Results: Low expression of miR-20a-5p (multivariate = 0.035) and miR-21-5p (multivariate = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37-0.89; = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32-0.83; = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, = 0.119; OS: HR 1.01; = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed.

Conclusion: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.
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http://dx.doi.org/10.3390/jcm9061663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355487PMC
June 2020

TNFα signalling predicts poor prognosis of patients with endometrial cancer.

Carcinogenesis 2020 Aug;41(8):1065-1073

Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.

Endometrial cancer (EC) is the most common gynaecologic tumour in the Western world. Previous studies have implicated an imbalance of oestrogens and progestogens in the development of most ECs, while the role of low-grade tissue inflammation remains largely unexplored. We investigated the impact of tumour necrosis factor alpha (TNFα), a central mediator of inflammation and spermatogenesis-associated protein 2 (SPATA2), a regulator of TNF receptor signalling, on clinical outcomes in EC. We evaluated TNFA and SPATA2 transcript levels in 239 EC patients and 25 non-malignant control tissues. Findings were validated in a cohort of 332 EC patients from The Cancer Genome Atlas (TCGA). Expression of TNFA and SPATA2 was increased in EC when compared with control tissues (P < 0.001). TNFA expression correlated with SPATA2 expression in non-malignant (P = 0.003, rS = 0.568) and EC tissue (P = 0.005, rS = 0.179). High TNFA and SPATA2 expression were associated with poor recurrence-free survival (RFS; P = 0.049 and P = 0.018) and disease-specific (P = 0.034 and P = 0.002) survival. Increased SPATA2 expression was also associated with decreased overall survival (OS; P = 0.013). In multivariate analysis, both TNFA and SPATA2 were predictors of clinical outcome. The impact of SPATA2 on RFS and OS could be validated in the TCGA cohort. Our study demonstrates that ECs exhibit a TNF signature which predicts clinical outcome. These findings indicate that TNF signalling modulates the course of EC, which could be therapeutically utilized in the future.
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http://dx.doi.org/10.1093/carcin/bgaa034DOI Listing
August 2020

The miR-34 family and its clinical significance in ovarian cancer.

J Cancer 2020 13;11(6):1446-1456. Epub 2020 Jan 13.

Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Tyrol, 6020, Austria.

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (=0.002, <0.001, <0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with mRNA-expression (BRCA1: miR34 b/c =0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and mRNA-expression (<0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in -mutated compared with -wild-type ovarian cancers (<0.001, =0.002, =0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, =0.033; miR-34b: HR 0.2, =0.001 and miR-34c: HR 0.3, =0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, =0.016) and miR-34c (HR 0.6, =0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.
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http://dx.doi.org/10.7150/jca.33831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995379PMC
January 2020

Toll-like receptor 3 mediates ischaemia/reperfusion injury after cardiac transplantation.

Eur J Cardiothorac Surg 2020 05;57(5):826-835

Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Objectives: Ischaemia and subsequent reperfusion during heart transplantation inevitably result in donor organ injury. Toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viral and endogenous RNA released by injured cells. We hypothesized that ischaemia/reperfusion injury (IRI) leads to RNA release with subsequent TLR3 activation in transplanted hearts.

Methods: Human endothelial cells were subjected to IRI and treated with TLR3 agonist polyinosinic-polycytidylic acid or a TLR3/double-stranded RNA complex inhibitor. TLR3 activation was analysed using reporter cells. Gene expression profiles were evaluated via next-generation sequencing. Neutrophil adhesion was assessed in vitro. Syngeneic heart transplantation of wild-type or Tlr3-/- mice was performed following 9 h of cold ischaemia. Hearts were analysed for inflammatory gene expression, cardiac damage, apoptosis and infiltrating leucocytes.

Results: IRI resulted in RNA release with subsequent activation of TLR3. Treatment with a TLR3 inhibitor abrogated the inflammatory response upon IRI. In parallel, TLR3 stimulation caused activation of the inflammasome. Endothelial IRI resulted in TLR3-dependent adhesion of neutrophils. Tlr3-/- animals showed reduced intragraft and splenic messenger ribonucleic acid (mRNA) expression of proinflammatory cytokines, resulting in decreased myocardial damage, apoptosis and infiltrating cells. Tlr3 deficiency protected from cardiac damage, apoptosis and leucocyte infiltration after cardiac transplantation.

Conclusions: We uncover the release of RNA by injured cells with subsequent activation of TLR3 as a crucial pathomechanism of IRI. Our data indicate that TLR3 represents a novel target in the prevention of IRI in solid organ transplantation.
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http://dx.doi.org/10.1093/ejcts/ezz383DOI Listing
May 2020

Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.

Leukemia 2020 06 3;34(6):1563-1576. Epub 2020 Jan 3.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m/day IV continuous infusion days 1-3, daunorubicin 45 mg/m IV days 1-3, etoposide 400 mg/m IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4 and CD8 peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4 and CD8 T cells.
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http://dx.doi.org/10.1038/s41375-019-0693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272276PMC
June 2020

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia.

Cell Death Dis 2019 12 10;10(12):944. Epub 2019 Dec 10.

Division of Oncology, Clinic of Medicine I, Medical University of Vienna, Vienna, Austria.

Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1 AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1 AML.
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http://dx.doi.org/10.1038/s41419-019-2172-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904467PMC
December 2019

The von Willebrand Factor Facilitates Model for End-Stage Liver Disease-Independent Risk Stratification on the Waiting List for Liver Transplantation.

Hepatology 2020 08 23;72(2):584-594. Epub 2020 Apr 23.

Division of General Surgery, Department of Surgery, Medical University of Vienna, General Hospital Vienna, Vienna, Austria.

Background And Aims: The Model for End-Stage Liver Disease (MELD) is used for clinical decision-making and organ allocation for orthotopic liver transplantation (OLT) and was previously upgraded through inclusion of serum sodium (Na) concentrations (MELD-Na). However, MELD-Na may underestimate complications arising from portal hypertension or infection. The von Willebrand factor (vWF) antigen (vWF-Ag) correlates with portal pressure and seems capable of predicting complications in patients with cirrhosis. Accordingly, this study aimed to evaluate vWF-Ag as an adjunct surrogate marker for risk stratification on the waiting list for OLT.

Approach And Results: Hence, WF-Ag at time of listing was assessed in patients listed for OLT. Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting-list survival was assessed by receiver operating characteristics and net reclassification improvement. Interestingly, patients dying within 3 months on the waiting list displayed elevated levels of vWF-Ag (P < 0.001). MELD-Na and vWF-Ag were comparable and independent in their predictive potential for 3-month mortality on the waiting list (area under the curve [AUC], vWF-Ag = 0.739; MELD-Na = 0.764). Importantly, a vWF-Ag cutoff at 413% identified patients at risk for death within 3 months of listing with a higher odds ratio (OR) than the previously published cutoff at a MELD-Na of 20 points (vWF-Ag, OR = 10.873, 95% confidence interval [CI], 3.160, 36.084; MELD-Na, OR = 7.594, 95% CI, 2.578, 22.372; P < 0.001, respectively). Ultimately, inclusion of vWF-Ag into the MELD-Na equation significantly improved prediction of 3-month waiting-list mortality (AUC, MELD-Na-vWF = 0.804).

Conclusions: A single measurement of vWF-Ag at listing for OLT predicts early mortality. Combining vWF-Ag levels with MELD-Na improves risk stratification and may help to prioritize organ allocation to decrease waiting-list mortality.
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http://dx.doi.org/10.1002/hep.31047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497135PMC
August 2020

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia.

Int J Mol Sci 2019 Nov 20;20(23). Epub 2019 Nov 20.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.
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http://dx.doi.org/10.3390/ijms20235826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928760PMC
November 2019

Sex matching does not impact the outcome after simultaneous pancreas-kidney transplantation.

Clin Transplant 2019 11 4;33(11):e13717. Epub 2019 Oct 4.

Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Background: Several studies in solid organ transplantation have shown a correlation between donor and recipient sex mismatch and risk of graft loss. In this study, we aimed to analyze the impact of donor and recipient sex matching on patient and pancreas graft survival in a large single-center cohort.

Methods: We retrospectively analyzed all first simultaneous pancreas-kidney transplants performed between 1979 and 2017 at the Medical University of Innsbruck.

Results: Of 452 patients, 54.6% (247) received a sex-matched transplant. Patient survival (P = .86), death-censored pancreas graft survival (dcPGS, P = .26), and death-censored kidney graft survival (dcKGS, P = .24) were similar between the sex-matched and sex-mismatched groups. Patient survival and dcPGS at 1, 5, and 15 years were 95.9%, 90.0%, and 62.1% and 86.1%, 77.1%, and 56.7% in the sex-matched group and 93.6%, 86.2%, and 62.4% and 83.1%, 73.3%, and 54.3% in the sex-mismatched group. Sex matching led to a lower odds of severe postoperative complications (41.2% vs 49.0%; OR 0.57, 95%CI 0.33-0.97; P = .038); however, no increased odds of other adverse postoperative outcomes was detected.

Conclusion: Our study demonstrates that sex matching reduced the odds of postoperative complications but did not impact other early and late outcome parameters in our cohort.
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http://dx.doi.org/10.1111/ctr.13717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899671PMC
November 2019

Outgrowth, proliferation, viability, angiogenesis and phenotype of primary human endothelial cells in different purchasable endothelial culture media: feed wisely.

Histochem Cell Biol 2019 Nov 21;152(5):377-390. Epub 2019 Sep 21.

Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria.

Function and dysfunction of endothelial cells are regulated by a multitude of factors. Endothelial cell research often requires in vitro cell culture experiments. Hence, various culture media specifically designed to promote endothelial cell growth are available. These strikingly differ in their composition: complex media contain endothelial cell growth supplement (ECGS), an extract produced of bovine brain with undefined amounts of biologically active compounds, whilst defined media contain selected growth factors in defined concentrations. We here compared the effect of seven purchasable endothelial cell culture media on colony outgrowth, proliferation, viability, in vitro angiogenesis and phenotype of mature primary human endothelial cells using feto-placental endothelial cells isolated from chorionic arteries (fpEC). The effect of media on colony outgrowth was additionally tested on umbilical cord blood-derived endothelial progenitor cells (ECFCs). Outgrowth, purity, proliferation and viability differed between media. Outgrowth of fpEC and ECFCs was best in a defined medium containing EGF, FGF2 and VEGF. By contrast, established fpEC isolations proliferated best in complex media containing ECGS, heparin and ascorbic acid. Also viability of cells was higher in complex media. In vitro angiogenesis was most intense in a defined medium containing the highest number of individual growth factors. FACS analysis of surface markers for endothelial cell subtypes revealed that endothelial phenotype of fpEC was unaffected by media composition. Our data demonstrate the fundamental effect of endothelial cell culture media on primary cell isolation success and behaviour. Whether the composition of supplements is suitable also for individual experiments needs to be tested specifically.
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http://dx.doi.org/10.1007/s00418-019-01815-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842357PMC
November 2019

Next-generation computational tools for interrogating cancer immunity.

Nat Rev Genet 2019 12 12;20(12):724-746. Epub 2019 Sep 12.

Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.

The remarkable success of cancer therapies with immune checkpoint blockers is revolutionizing oncology and has sparked intensive basic and translational research into the mechanisms of cancer-immune cell interactions. In parallel, numerous novel cutting-edge technologies for comprehensive molecular and cellular characterization of cancer immunity have been developed, including single-cell sequencing, mass cytometry and multiplexed spatial cellular phenotyping. In order to process, analyse and visualize multidimensional data sets generated by these technologies, computational methods and software tools are required. Here, we review computational tools for interrogating cancer immunity, discuss advantages and limitations of the various methods and provide guidelines to assist in method selection.
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http://dx.doi.org/10.1038/s41576-019-0166-7DOI Listing
December 2019

miR-19a-3p containing exosomes improve function of ischaemic myocardium upon shock wave therapy.

Cardiovasc Res 2020 05;116(6):1226-1236

Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.

Aims: As many current approaches for heart regeneration exert unfavourable side effects, the induction of endogenous repair mechanisms in ischaemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of reparative exosomes in ischaemic myocardium. In the present study, we sought to test the hypothesis that the physical stimulus of shock wave therapy (SWT) causes the release of exosomes. We aimed to substantiate the pro-angiogenic impact of the released factors, to identify the nature of their cargo, and to test their efficacy in vivo supporting regeneration and recovery after myocardial ischaemia.

Methods And Results: Mechanical stimulation of ischaemic muscle via SWT caused extracellular vesicle (EV) release from endothelial cells both in vitro and in vivo. Characterization of EVs via electron microscopy, nanoparticle tracking analysis and flow cytometry revealed specific exosome morphology and size with the presence of exosome markers CD9, CD81, and CD63. Exosomes exhibited angiogenic properties activating protein kinase b (Akt) and extracellular-signal regulated kinase (ERK) resulting in enhanced endothelial tube formation and proliferation. A miRNA array and transcriptome analysis via next-generation sequencing were performed to specify exosome content. miR-19a-3p was identified as responsible cargo, antimir-19a-3p antagonized angiogenic exosome effects. Exosomes and target miRNA were injected intramyocardially in mice after left anterior descending artery ligation. Exosomes resulted in improved vascularization, decreased myocardial fibrosis, and increased left ventricular ejection fraction as shown by transthoracic echocardiography.

Conclusion: The mechanical stimulus of SWT causes release of angiogenic exosomes. miR-19a-3p is the vesicular cargo responsible for the observed effects. Released exosomes induce angiogenesis, decrease myocardial fibrosis, and improve left ventricular function after myocardial ischaemia. Exosome release via SWT could develop an innovative approach for the regeneration of ischaemic myocardium.
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http://dx.doi.org/10.1093/cvr/cvz209DOI Listing
May 2020

Correction to: Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data.

Genome Med 2019 Jul 29;11(1):50. Epub 2019 Jul 29.

Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innrain 80, Innsbruck, Austria.

It was highlighted that the original article [1] contained a typesetting mistake in the name of Noel Filipe da Cunha Carvalho de Miranda. This was incorrectly captured as Noel Filipe da Cunha Carvahlo de Miranda. It was also highlighted that in Fig. 3C the left panels Y-axis were cropped and in Fig. 5C, CD8 bar was cropped. This Correction article shows the correct Figs. 3 and 5. The original article has been updated.
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http://dx.doi.org/10.1186/s13073-019-0655-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661746PMC
July 2019

Baseline Absolute Lymphocyte Count and ECOG Performance Score Are Associated with Survival in Advanced Non-Small Cell Lung Cancer Undergoing PD-1/PD-L1 Blockade.

J Clin Med 2019 Jul 10;8(7). Epub 2019 Jul 10.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, Austria.

Immune-checkpoint blockade in front-line or second-line treatment improves survival in advanced non-small cell lung cancer (aNSCLC) when compared with chemotherapy alone. However, easily applicable predictive parameters are necessary to guide immune-checkpoint inhibition in clinical practice. In this retrospective bi-centric analysis, we investigated the impact of baseline patient and tumor characteristics on clinical outcome in aNSCLC patients treated with programmed cell death protein 1(PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. Between May 2015 and January 2018, 142 unselected consecutive NSCLC patients received PD-1/PD-L1 inhibitors during the course of disease. In multivariate analysis, we identified the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG > 1 versus ECOG ≤ 1, HR: 3.23, 95%CI: 1.58-6.60, = 0.001), baseline absolute lymphocyte count (ALC; high: >0.93 × 10/L versus low: ≤ 0.93 × 10/L, HR: 0.38, 95%CI: 0.23-0.62, < 0.001), prior or concomitant anti-vascular endothelial growth factor (VEGF) targeting therapy (yes versus no, HR: 2.18, 95%CI: 1.15-4.14, = 0.017) and TNM stage (IV versus III, HR: 4.18, 95%CI: 1.01-17.36, = 0.049) as the most relevant parameters for survival. Neither antibiotic exposure (antibiotic-positive versus antibiotic-negative, HR: 0.90, 95%CI: 0.56-1.45, = 0.675), nor PD-L1 expression on tumor cells (≥1% versus <1%, HR: 0.68, 95%CI: 0.41-1.13, = 0.140) was associated with survival. Baseline ECOG performance status and ALC were associated with survival in aNSCLC patients treated with PD-1/PD-L1 inhibitors and assessment of these parameters could be suitable in clinical practice.
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http://dx.doi.org/10.3390/jcm8071014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678702PMC
July 2019

SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness.

Sci Rep 2019 06 24;9(1):9139. Epub 2019 Jun 24.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to its genetic and molecular basis and to patients´ outcome. Clinical, cytogenetic, and mutational data are used to classify patients into risk groups with different survival, however, within-group heterogeneity is still an issue. Here, we used a robust likelihood-based survival modeling approach and publicly available gene expression data to identify a minimal number of genes whose combined expression values were prognostic of overall survival. The resulting gene expression signature (4-GES) consisted of 4 genes (SOCS2, IL2RA, NPDC1, PHGDH), predicted patient survival as an independent prognostic parameter in several cohorts of AML patients (total, 1272 patients), and further refined prognostication based on the European Leukemia Net classification. An oncogenic role of the top scoring gene in this signature, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML. SOCS2 promoted leukemogenesis as well as the abundance, quiescence, and activity of AML stem cells. Overall, the 4-GES represents a highly discriminating prognostic parameter in AML, whose clinical applicability is greatly enhanced by its small number of genes. The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically.
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http://dx.doi.org/10.1038/s41598-019-45579-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591510PMC
June 2019

Clinical Impact of RANK Signalling in Ovarian Cancer.

Cancers (Basel) 2019 Jun 8;11(6). Epub 2019 Jun 8.

Department of Obstetrics and Gynaecology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. , and expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. expression was elevated in OC tissue, particularly in mutated tumours. High expression independently predicted reduced progression-free (PFS, = 0.017) and overall survival (OS, = 0.007), which could be validated in the TCGA cohort (PFS, = 0.022; OS, = 0.046, respectively). Expression of and in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.
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http://dx.doi.org/10.3390/cancers11060791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627676PMC
June 2019

Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data.

Genome Med 2019 05 24;11(1):34. Epub 2019 May 24.

Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innrain 80, Innsbruck, Austria.

We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry, and immunohistochemistry data.quanTIseq analysis of 8000 tumor samples revealed that cytotoxic T cell infiltration is more strongly associated with the activation of the CXCR3/CXCL9 axis than with mutational load and that deconvolution-based cell scores have prognostic value in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture and to reveal immune-cell types that underlie differential patients' responses to checkpoint blockers.Availability: quanTIseq is available at http://icbi.at/quantiseq .
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http://dx.doi.org/10.1186/s13073-019-0638-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534875PMC
May 2019

Regorafenib Is Associated With Increased Skeletal Muscle Loss Compared to TAS-102 in Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2019 06 11;18(2):159-166.e3. Epub 2019 Apr 11.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology, and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute, Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, Salzburg, Austria. Electronic address:

Background: Current guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology recommend regorafenib or trifluridine/tipiracil (TAS-102) for third-line therapy of metastatic colorectal cancer (mCRC). We evaluated the impact of regorafenib and TAS-102 treatment on skeletal muscle dynamics and sarcopenia.

Patients And Methods: This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 during third or later line of therapy at our tertiary-care cancer center in Salzburg, Austria. The skeletal muscle index (SMI, cm/m) and sarcopenia were evaluated from cross-sectional computed tomographic images at the level of the third lumbar vertebra.

Results: Between January 2013 and April 2018, a total of 45 patients had received regorafenib and/or TAS-102. At initial mCRC diagnosis and at initiation of third-line therapy, 24% and 54% of patients presented with sarcopenia. A statistically significant skeletal muscle loss was observed during regorafenib treatment (median SMI change: -2.75 cm/m [-6.3%]; P < .0001), which was not the case during TAS-102 therapy (-1.5 cm/m [-3.5%]; P = .575). Furthermore, subclassification of patients into 3 groups-normal muscle mass, stable sarcopenia, and new-onset sarcopenia-at initiation of third-line therapy permitted discrimination of overall survival, with 1-year overall survival rates of 61%, 29%, and 16%, respectively (P = .04).

Conclusion: The frequency of sarcopenia increases during the course of mCRC and negatively affects survival. In contrast to TAS-102, regorafenib is associated with increased skeletal muscle loss during mCRC treatment and should therefore be used with caution in mCRC patients with preexisting sarcopenia or a history of recent weight loss.
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http://dx.doi.org/10.1016/j.clcc.2019.04.003DOI Listing
June 2019