Publications by authors named "Michael Bergmann"

94 Publications

Visible blue light inhibits infection and replication of SARS-CoV-2 at doses that are well-tolerated by human respiratory tissue.

Sci Rep 2021 10 18;11(1):20595. Epub 2021 Oct 18.

EmitBio Inc., 4222 Emperor Blvd, Suite 470, Durham, NC, 27703, USA.

The delivery of safe, visible wavelengths of light can be an effective, pathogen-agnostic, countermeasure that would expand the current portfolio of SARS-CoV-2 intervention strategies beyond the conventional approaches of vaccine, antibody, and antiviral therapeutics. Employing custom biological light units, that incorporate optically engineered light-emitting diode (LED) arrays, we harnessed monochromatic wavelengths of light for uniform delivery across biological surfaces. We demonstrated that primary 3D human tracheal/bronchial-derived epithelial tissues tolerated high doses of a narrow spectral band of visible light centered at a peak wavelength of 425 nm. We extended these studies to Vero E6 cells to understand how light may influence the viability of a mammalian cell line conventionally used for assaying SARS-CoV-2. The exposure of single-cell monolayers of Vero E6 cells to similar doses of 425 nm blue light resulted in viabilities that were dependent on dose and cell density. Doses of 425 nm blue light that are well-tolerated by Vero E6 cells also inhibited infection and replication of cell-associated SARS-CoV-2 by > 99% 24 h post-infection after a single five-minute light exposure. Moreover, the 425 nm blue light inactivated cell-free betacoronaviruses including SARS-CoV-1, MERS-CoV, and SARS-CoV-2 up to 99.99% in a dose-dependent manner. Importantly, clinically applicable doses of 425 nm blue light dramatically inhibited SARS-CoV-2 infection and replication in primary human 3D tracheal/bronchial tissue. Safe doses of visible light should be considered part of the strategic portfolio for the development of SARS-CoV-2 therapeutic countermeasures to mitigate coronavirus disease 2019 (COVID-19).
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http://dx.doi.org/10.1038/s41598-021-99917-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523529PMC
October 2021

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematological Cancers and Identifies Exceptional Responders.

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

Platform Austria for Chemical Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients' tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0538DOI Listing
October 2021

Telocytes in the human ascending aorta: Characterization and exosome-related KLF-4/VEGF-A expression.

J Cell Mol Med 2021 10 25;25(20):9697-9709. Epub 2021 Sep 25.

Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.

Telocytes (TCs), a novel interstitial cell entity promoting tissue regeneration, have been described in various tissues. Their role in inter-cellular signalling and tissue remodelling has been reported in almost all human tissues. This study hypothesizes that TC also contributes to tissue remodelling and regeneration of the human thoracic aorta (HTA). The understanding of tissue homeostasis and regenerative potential of the HTA is of high clinical interest as it plays a crucial role in pathogenesis from aortic dilatation to lethal dissection. Therefore, we obtained twenty-five aortic specimens of heart donors during transplantation. The presence of TCs was detected in different layers of aortic tissue and characterized by immunofluorescence and transmission electron microscopy. Further, we cultivated and isolated TCs in highly differentiated form identified by positive staining for CD34 and c-kit. Aortic-derived TC was characterized by the expression of PDGFR-α, PDGFR-β, CD29/integrin β-1 and αSMA and the stem cell markers Nanog and KLF-4. Moreover, TC exosomes were isolated and characterized for soluble angiogenic factors by Western blot. CD34 /c-kit TCs shed exosomes containing the soluble factors VEGF-A, KLF-4 and PDGF-A. In summary, TC occurs in the aortic wall. Correspondingly, exosomes, derived from aortic TCs, contain vasculogenesis-relevant proteins. Understanding the regulation of TC-mediated aortic remodelling may be a crucial step towards designing strategies to promote aortic repair and prevent adverse remodelling.
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http://dx.doi.org/10.1111/jcmm.16919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505852PMC
October 2021

Systematic review of the immunological landscape of Wilms tumors.

Mol Ther Oncolytics 2021 Sep 13;22:454-467. Epub 2021 Jul 13.

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

Results of immunotherapy in childhood solid cancer have been so far, with the exception of neuroblastoma, quite disappointing. Lack of knowledge of the immune contexture of these tumors may have contributed to the failure of immunotherapies so far. Here, we systematically reviewed the literature regarding the immunology of Wilms tumor (WT), one of the most frequent pediatric solid tumors of the abdomen. In Wilms tumor patients the high cure rate of >90%, achieved by the combination of surgery and radio-chemotherapy, is at the expense of a high early and late toxicity. Moreover, treatment-resistant entities, such as diffuse anaplastic tumors or recurrent disease, still pose unsolved clinical problems. Successful immunotherapy could represent a novel and possibly less-toxic treatment option. Employing the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) method of literature search, we analyzed the current knowledge of the immunological landscape of Wilms tumors in terms of tumor microenvironment, prognostic implications of single biomarkers, and immunotherapy response.
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http://dx.doi.org/10.1016/j.omto.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430048PMC
September 2021

Fractionated stereotactic radiotherapy for uveal melanoma: Long-term outcome and control rates.

Acta Ophthalmol 2021 Sep 16. Epub 2021 Sep 16.

Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Purpose: The aim of our study is to evaluate local tumour control rates, radiation side-effects, visual preservation and disease-free survival (DFS) of uveal melanoma (UM) patients treated with fractionated stereotactic radiotherapy (fSRT).

Methods: A retrospective study of UM patients, who were treated with fSRT (N = 189), was performed by the Rotterdam Ocular Melanoma Study group (ROMS), the Netherlands, between 1999 and 2014 with a follow-up of at least 5 years.

Results: The 1-, 3-, 5-, 10- and 15-year local tumour control rates were as follows: 99.4%, 92.8%, 92.2%, 89.3% and 89.3%, respectively. Cataract (67.8%) was the most common side-effect of fSRT followed by retinopathy (35.1%), maculopathy (23.8%), vitreous haemorrhage (20.1%), neovascular glaucoma (NVG) (20.0%) and optic neuropathy (12.4%). Patients with anterior located UMs developed cataract more frequently (p = 0.047, multivariable analysis). By multivariable analysis, significant factors for secondary enucleation were tumour recurrence (p < 0.001) and NVG (p < 0.001). In multivariable analysis, risk factors for a worse DFS were larger UM (p = 0.024) and tumours with subretinal fluid (SRF) at baseline (p = 0.038). The 5-year DFS was 77.0% and the best corrected visual acuity decreased significantly after treatment. After 5 years, 22.0% of patients and after 10 years 17.6% of patients had a visual acuity of ≤0.3 logMAR.

Conclusion: Fractionated stereotactic radiotherapy is a good treatment option for small-, medium- and large-sized tumours with 5-year local tumour control of 92.2%. After 5 years, 22.0% of the patients had a good vision. Independently of tumour location, the visual acuity decreased significantly after treatment. Overall, the 5-year DFS was 77.0%.
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http://dx.doi.org/10.1111/aos.15029DOI Listing
September 2021

Estimation of exogenous drivers to predict COVID-19 pandemic using a method from nonlinear control theory.

Nonlinear Dyn 2021 Sep 6:1-15. Epub 2021 Sep 6.

Institute of Mechanics and Mechatronics, TU Wien, Getreidemarkt 9, 1060 Vienna, Austria.

The currently ongoing COVID-19 pandemic confronts governments and their health systems with great challenges for disease management. Epidemiological models play a crucial role, thereby assisting policymakers to predict the future course of infections and hospitalizations. One difficulty with current models is the existence of exogenous and unmeasurable variables and their significant effect on the infection dynamics. In this paper, we show how a method from nonlinear control theory can complement common compartmental epidemiological models. As a result, one can estimate and predict these exogenous variables requiring the reported infection cases as the only data source. The method allows to investigate how the estimates of exogenous variables are influenced by non-pharmaceutical interventions and how imminent epidemic waves could already be predicted at an early stage. In this way, the concept can serve as an "epidemometer" and guide the optimal timing of interventions. Analyses of the COVID-19 epidemic in various countries demonstrate the feasibility and potential of the proposed approach. The generic character of the method allows for straightforward extension to different epidemiological models.
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http://dx.doi.org/10.1007/s11071-021-06811-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419820PMC
September 2021

Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial.

J Am Soc Nephrol 2021 08;32(8):2083-2098

Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Background: Post-transplantation diabetes mellitus (PTDM) might be preventable.

Methods: This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant.

Results: In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24.

Conclusions: At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study. NCT03507829.
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http://dx.doi.org/10.1681/ASN.2021010127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455276PMC
August 2021

Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages.

Cancer Lett 2021 Nov 10;520:184-200. Epub 2021 Jul 10.

Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria. Electronic address:

Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major components of the tumor microenvironment. TAMs promote tumor progression, angiogenesis and tissue remodeling. However, the impact of the molecular crosstalk of tumor cells (TCs) with CAFs and macrophages on monocyte recruitment and their phenotypic conversion is not known in detail so far. In a 3D human organotypic CRC model, we show that CAFs and normal colonic fibroblasts are critically involved in monocyte recruitment and for the establishment of a macrophage phenotype, characterized by high CD163 expression. This is in line with the steady recruitment and differentiation of monocytes to immunosuppressive macrophages in the normal colon. Cytokine profiling revealed that CAFs produce M-CSF, and IL6, IL8, HGF and CCL2 secretion was specifically induced by CAFs in co-cultures with macrophages. Moreover, macrophage/CAF/TCs co-cultures increased TC invasion. We demonstrate that CAFs and macrophages are the major producers of CCL2 and, upon co-culture, increase their CCL2 production twofold and 40-fold, respectively. CAFs and macrophages expressing high CCL2 were also found in vivo in CRC, strongly supporting our findings. CCL2, CCR2, CSF1R and CD163 expression in macrophages was dependent on active MCSFR signaling as shown by M-CSFR inhibition. These results indicate that colon fibroblasts and not TCs are the major cellular component, recruiting and dictating the fate of infiltrated monocytes towards a specific macrophage population, characterized by high CD163 expression and CCL2 production.
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http://dx.doi.org/10.1016/j.canlet.2021.07.006DOI Listing
November 2021

The Impact of COVID-19 on Informal Caregiving and Care Receiving Across Europe During the First Phase of the Pandemic.

Front Public Health 2021 16;9:673874. Epub 2021 Jun 16.

Munich Center for the Economics of Aging, Max Planck Institute for Social Law and Social Policy, Munich, Germany.

We analyzed the effects of COVID-19 as well as its accompanying epidemiological control measures on health-related outcomes (physical and mental health) and unmet care needs of both caregivers and care recipients across Europe and Israel by taking into account country differences. We applied comparisons of adjusted predictions, controlling for a large set of relevant respondent characteristics, to investigate changes in the physical and mental health of caregivers and care recipients due to COVID-19. Furthermore, multilevel regression models were used to analyze the effect of individual and contextual indicators on the probability of reporting difficulties in receiving care. For the analyses, we used data from 26 countries with 51,983 respondents over 50 years based on the eighth wave of the Survey of Health, Aging and Retirement in Europe (SHARE), which had to be suspended in March 2020, and the SHARE Corona Survey fielded from June to August 2020. During the first phase of the pandemic in spring/summer 2020, the frequency of providing personal care to parents increased in almost all European countries, while care to children, in turn, decreased. Parental caregivers who increased the frequency of providing personal care reported significantly more mental health strains, that is, feeling sad/depressed and anxious/nervous more often since the outbreak of the pandemic. With respect to receiving care, about one out of five care recipients had difficulty in obtaining adequate care from outside the household during the pandemic. The perception of unmet care needs was significantly associated with country differences regarding the duration of the stay-at-home orders. In contrast, the number of confirmed deaths did not have a significant effect on perceiving difficulties related to receiving care. Our findings show the extent of the burden to which caregivers and care recipients were exposed with respect to the unintended consequences of COVID-19-related epidemiological control measures. There is a great need within this population for interventions, which effectively reduce the burden as well as the symptoms of anxiety or depression for caregivers as well as care recipients. This should be recognized by (health) policymakers and social organizations.
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http://dx.doi.org/10.3389/fpubh.2021.673874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242257PMC
July 2021

Serological responses to koi herpesvirus (KHV) in a non-cyprinid reservoir host.

J Fish Dis 2021 Aug 11;44(8):1229-1236. Epub 2021 May 11.

Aquatic Vaccine Unit, School of Natural Sciences, Institute of Aquaculture, University of Stirling, Stirling, UK.

Koi herpesvirus (KHV) is a highly contagious virus that causes KHV disease (KHVD) inducing high mortality in carp and koi (Cyprinus carpio L.). In the late stage, latency occurs with very low, often non-detectable virus concentrations, which represents a challenge for virus detection. After validation according to OIE recommendations, an antibody ELISA was established to recognize antibodies of C. carpio against KHV infection. In this study, the ELISA was modified to detect anti-KHV antibodies from a non-cyprinid fish. Experimentally infected rainbow trout (Oncorhynchus mykiss) were able to transmit KHV to naïve carp at two different temperatures, demonstrating their potential as a reservoir host. At 20°C, KHVD was induced in carp but not at 15°C. Unexpectedly, rainbow trout developed humoral response against KHV at both temperatures. In contrast to carp, at 15°C trout produced neutralizing antibodies but not at 20°C. While antibodies obtained from infected carp sera reacted in a similar way against all KHV, antibodies from rainbow trout sera reacted differently to the same isolates by ELISA. The data show that even when non-cyprinid fish species are infected with KHV, they can produce antibodies that differ from those observed in carp.
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http://dx.doi.org/10.1111/jfd.13385DOI Listing
August 2021

Bodyweight change and cognitive performance in the older population.

PLoS One 2021 21;16(4):e0249651. Epub 2021 Apr 21.

Munich Center for the Economics of Aging (MEA), Max Planck Institute for Social Law and Social Policy, Munich, Germany.

Preservation of cognitive function is one of the major concerns in contemporary ageing societies. At the same time, overweight and obesity, which have been identified as risk factors for poor health development, have been increasing in many countries all over the world. This study examines the relationship between bodyweight change and cognitive decline in old age and it aims to determine whether and how changes in body mass index (BMI) affect the development of cognitive functioning in old age. Using longitudinal data from the Survey of Health, Ageing and Retirement in Europe (SHARE), covering four waves between 2006 and 2016 with 58,389 participants from 15 countries aged 50+, we estimated asymmetric fixed effects models by gender, adding possible confounding variables such as age, grip strength, health conditions, and physical activity. Additionally, we investigated possible heterogeneity in the BMI-cognition relation. We found a positive association between BMI change and change in cognitive performance, which was dominantly driven by BMI decrease. Weight loss was typically negatively related to cognition, particularly at low levels of BMI and mainly due to health conditions affecting both bodyweight and cognitive performance. Weight gain was, on average, not significantly related to cognitive performance; only respondents with preceding weight loss profited from small increases in BMI. Our analyses provide no support for an "obesity paradox" in cognition, according to which higher weight preserves cognition in old age. The association between weight change and cognitive performance in older age is based on weight changes being related to illness and recovery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249651PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059803PMC
September 2021

Surgical Complexity and Outcome During the Implementation Phase of a Robotic Colorectal Surgery Program-A Retrospective Cohort Study.

Front Oncol 2020 16;10:603216. Epub 2021 Feb 16.

Department of Surgery, Division of General Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

Background: Robotic surgery holds particular promise for complex oncologic colorectal resections, as it can overcome many limitations of the laparoscopic approach. However, similar to the situation in laparoscopic surgery, appropriate case selection (simple vs. complex) with respect to the actual robotic expertise of the team may be a critical determinant of outcome. The present study aimed to analyze the clinical outcome after robotic colorectal surgery over time based on the complexity of the surgical procedure.

Methods: All robotic colorectal resections (n = 85) performed at the Department of Surgery, Medical University of Vienna, between the beginning of the program in April 2015 until December 2019 were retrospectively analyzed. To compare surgical outcome over time, the cohort was divided into 2 time periods based on case sequence (period 1: patients 1-43, period 2: patients 44-85). Cases were assigned a complexity level (I-IV) according to the type of resection, severity of disease, sex and body mass index (BMI). Postoperative complications were classified using the Clavien-Dindo classification.

Results: In total, 47 rectal resections (55.3%), 22 partial colectomies (25.8%), 14 abdomino-perineal resections (16.5%) and 2 proctocolectomies (2.4%) were performed. Of these, 69.4% (n = 59) were oncologic cases. The overall rate of major complications (Clavien Dindo III-V) was 16.5%. Complex cases (complexity levels III and IV) were more often followed by major complications than cases with a low to medium complexity level (I and II; 25.0 vs. 5.4%, p = 0.016). Furthermore, the rate of major complications decreased over time from 25.6% (period 1) to 7.1% (period 2, p = 0.038). Of note, the drop in major complications was associated with a learning effect, which was particularly pronounced in complex cases as well as a reduction of case complexity from 67.5% to 45.2% in the second period (p = 0.039).

Conclusions: The risk of major complications after robotic colorectal surgery increases significantly with escalating case complexity (levels III and IV), particularly during the initial phase of a new colorectal robotic surgery program. Before robotic proficiency has been achieved, it is therefore advisable to limit robotic colorectal resection to cases with complexity levels I and II in order to keep major complication rates at a minimum.
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http://dx.doi.org/10.3389/fonc.2020.603216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923881PMC
February 2021

Long-termmonitoring of gliotic sheathing of ultrathin entropic coated brain microprobes with fiber-based optical coherence tomography.

J Neural Eng 2021 03 23;18(4). Epub 2021 Mar 23.

Section for Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.

Microfabricated neuroprosthetic devices have made possible important observations on neuron activity; however, long-term high-fidelity recording performance of these devices has yet to be realized. Tissue-device interactions appear to be a primary source of lost recording performance. The current state of the art for visualizing the tissue response surrounding brain implants in animals is immunohistochemistry + confocal microscopy, which is mainly performed after sacrificing the animal. Monitoring the tissue response as it develops could reveal important features of the response which may inform improvements in electrode design.Optical coherence tomography (OCT), an imaging technique commonly used in ophthalmology, has already been adapted for imaging of brain tissue. Here, we use OCT to achieve real-time,monitoring of the tissue response surrounding chronically implanted neural devices. The employed tissue-response-provoking implants are coated with a plasma-deposited nanofilm, which has been demonstrated as a biocompatible and anti-inflammatory interface for indwelling devices. We evaluate the method by comparing the OCT results to traditional histology qualitatively and quantitatively.The differences in OCT signal across the implantation period between the plasma group and the control reveal that the plasma-type coating of otherwise rigid brain probes (glass) only slightly improve the glial encapsulation in the brain parenchyma indicating that geometrical or mechanical influences are dominating the encapsulation process.Our approach can long-term monitor and compare the tissue-response to chronically-implanted neural probes with and withour plasma coating in living animal models. Our findings provide valuable insigh to the well acknowledged yet not solved challenge.
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http://dx.doi.org/10.1088/1741-2552/abebc2DOI Listing
March 2021

A 310 nm Optically Pumped AlGaN Vertical-Cavity Surface-Emitting Laser.

ACS Photonics 2021 Jan 17;8(1):135-141. Epub 2020 Dec 17.

Department of Microtechnology and Nanoscience, Chalmers University of Technology, 41296 Gothenburg, Sweden.

Ultraviolet light is essential for disinfection, fluorescence excitation, curing, and medical treatment. An ultraviolet light source with the small footprint and excellent optical characteristics of vertical-cavity surface-emitting lasers (VCSELs) may enable new applications in all these areas. Until now, there have only been a few demonstrations of ultraviolet-emitting VCSELs, mainly optically pumped, and all with low Al-content AlGaN cavities and emission near the bandgap of GaN (360 nm). Here, we demonstrate an optically pumped VCSEL emitting in the UVB spectrum (280-320 nm) at room temperature, having an AlGaN cavity between two dielectric distributed Bragg reflectors. The double dielectric distributed Bragg reflector design was realized by substrate removal using electrochemical etching. Our method is further extendable to even shorter wavelengths, which would establish a technology that enables VCSEL emission from UVA (320-400 nm) to UVC (<280 nm).
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http://dx.doi.org/10.1021/acsphotonics.0c01382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821306PMC
January 2021

Determinants of Physical Activity and Sedentary Behavior in German Elementary School Physical Education Lessons.

Front Sports Act Living 2020 15;2:113. Epub 2020 Sep 15.

Department of Sport and Health Sciences, Technical University of Munich, Munich, Germany.

Physical activity (PA) in school physical education (PE) is a signature component of health promotion and health education. The study's aim was to explore PA levels and sedentary time in German elementary school PE lessons and relate them to selected personal and environmental PA determinants. Accelerometer measurements were collected from 328 students (47% male, mean age 8.7 ± 1.2 years) in 11 elementary schools in Baden-Wuerttemberg (Germany). PA levels and sedentary time were analyzed regarding gender, grade, body mass index, selected correlates of active living and health behaviors, as well as the PE teachers' PE education status. In line with previous research, the analyses of PA levels and sedentary time confirm gender and grade differences and highlight older girls as the less active group. Deviant weight status and parents' PA levels were found to be important determinants for PA levels and sedentary time of girls and offer starting points for intervention studies as well as gender-appropriate PE in elementary schools. Specialist PE teacher status proved to be a negative determinant of PA levels and sedentary time for boys and girls and should be investigated in further studies, especially regarding the didactic and methodological background.
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http://dx.doi.org/10.3389/fspor.2020.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739767PMC
September 2020

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

JNCI Cancer Spectr 2020 Oct 7;4(5):pkaa051. Epub 2020 Jul 7.

Department of Surgery, Hospital Group Twente ZGT, Almelo, the Netherlands.

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.

Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.

Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.

Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.
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http://dx.doi.org/10.1093/jncics/pkaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583160PMC
October 2020

The Immune Phenotype of Isolated Lymphoid Structures in Non-Tumorous Colon Mucosa Encrypts the Information on Pathobiology of Metastatic Colorectal Cancer.

Cancers (Basel) 2020 Oct 25;12(11). Epub 2020 Oct 25.

Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria.

The gut-associated lymphoid tissue represents an integral part of the immune system. Among the powerful players of the mucosa-associated lymphoid tissue are isolated lymphoid structures (ILSs), which as information centers, drive the local (and systemic) adaptive immune responses. Germinal center reactions, taking place within ILSs, involve the coordinated action of various immune cell types with a central role given to B cells. In the current study, we aimed at dissecting the impact of ILSs within non-tumorous colon tissue (NT) on the pathobiology of colorectal cancer (CRC) with metastasis in the liver (CRCLM). In particular, we focused on the immune phenotypes of ILSs and ectopic lymphoid structures (ELSs), built up at matching primary and metastatic tumor sites. We implemented an integrative analysis strategy on the basis of tissue image cytometry and clonality assessment to explore the immune phenotype of ILS/ELS at three tissue entities: NT, CRC, and CRCLM (69 specimens in total). Applying a panel of lineage markers used for immunostaining, we characterized and compared the anatomical features, the cellular composition, the activation, and proliferation status of ILSs and ELSs, and assessed the clinical relevance of staining-derived data sets. Our major discovery was that ILS characteristics at the NT site predefine the immune phenotype of ELSs at CRC and CRCLM. Thereby, B-cell-enriched (CD20) and highly proliferative (Ki67) ILSs and ELSs were found to be associated with improved clinical outcome in terms of survival and enabled patient stratification into risk groups. Moreover, the data revealed a linkage between B-cell clonality at the NT site and the metastatic characteristics of the tumor in the distant liver tissue. Consolidation of immunostaining-based findings with the results of compendium-wide transcriptomic analysis furthermore proposed CD27 as a novel marker of T follicular helper cells within lymphoid structures. Overall, the study nominates the ILS immune phenotype as a novel prognostic marker for patients with metastatic CRC.
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http://dx.doi.org/10.3390/cancers12113117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692185PMC
October 2020

Short-course radiotherapy promotes pro-inflammatory macrophages via extracellular vesicles in human rectal cancer.

J Immunother Cancer 2020 08;8(2)

Department of Visceral Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Vienna, Austria

Background: Tumor-associated macrophages (TAM) constitute the most abundant immune cells in the tumor stroma initiating pro-inflammatory (M1) or immunosuppressive (M2) responses depending on their polarization status. Advances in tumor immunotherapy call for a detailed understanding of potential immunogenic mechanisms of irradiation routinely applied in rectal cancer patients.

Methods: To test the effects of radiotherapy on TAM, we ex vivo irradiated tissue samples of human rectal cancer and assessed the phenotype by flow cytometry. We furthermore evaluated the distribution of leucocyte subsets in tissue sections of patients after short-course radiotherapy and compared findings to non-pretreated rectal cancer using an immunostaining approach. Organotypic assays (OTA) consisting of macrophages, cancer-associated fibroblast and cancer cell lines were used to dissect the immunological consequences of irradiation in macrophages.

Results: We demonstrate that short-course neoadjuvant radiotherapy in rectal cancer patients is associated with a shift in the polarization of TAM towards an M1-like pro-inflammatory phenotype. In addition, ex vivo irradiation caused an increase in the phagocytic activity and enhanced expression of markers associated with stimulatory signals necessary for T-cell activation. In OTA we observed that this alteration in macrophage polarization could be mediated by extracellular vesicles (EV) derived from irradiated tumor cells. We identified high mobility group box 1 in EV from irradiated tumor cells as a potential effector signal in that crosstalk.

Conclusions: Our findings highlight macrophages as potential effector cells upon irradiation in rectal cancer by diminishing their immunosuppressive phenotype and activate pro-inflammation. Our data indicate that clinically applied short-term radiotherapy for rectal cancer may be exploited to stimulate immunogenic macrophages and suggest to target the polarization status of macrophages to enhance future immunotherapeutic strategies.
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http://dx.doi.org/10.1136/jitc-2020-000667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437887PMC
August 2020

From threat to cure: understanding of virus-induced cell death leads to highly immunogenic oncolytic influenza viruses.

Cell Death Discov 2020 11;6:48. Epub 2020 Jun 11.

Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Oncolytic viruses constitute an emerging strategy in immunomodulatory cancer treatment. The first oncolytic virus, Talimogene laherparepvec (T-VEC), based on herpes simplex virus 1 (HSV-1), was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2015. The field of oncolytic virotherapy is still in its beginnings, since many promising viruses remain only superficially explored. Influenza A virus causes a highly immunogenic acute infection but never leads to a chronic disease. While oncolytic influenza A viruses are in preclinical development, they have not made the transition into clinical practice yet. Recent insights into different types of cell death caused by influenza A virus infection illuminate novel possibilities of enhancing its therapeutic effect. Genetic engineering and experience in influenza A virus vaccine development allow safe application of the virus in patients. In this review we give a summary of efforts undertaken to develop oncolytic influenza A viruses. We discuss strategies for targeting viral replication to cancerous lesions and arming them with immunogenic transgenes. We furthermore describe which modes of cell death are induced by influenza A virus infection and how these insights may be utilized to optimize influenza A virus-based oncolytic virus design.
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http://dx.doi.org/10.1038/s41420-020-0284-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288254PMC
June 2020

Crohn's disease: prevalence, MR features, and clinical significance of enteric and colonic sinus tracts.

Eur Radiol 2020 Oct 26;30(10):5358-5366. Epub 2020 May 26.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Objectives: Enteric and colonic sinus tracts are inflammatory complications that precede intestinal fistulas in patients with Crohn's disease (CD). The aim of this study was to retrospectively determine the prevalence, morphologic features, and outcome of sinus tracts using MR imaging.

Methods: A consecutive cohort of 642 patients with known CD, referred for MR enterography or MR enteroclysis (study period 01/2014-09/2019), was evaluated retrospectively for the presence of sinus tracts, their locations, presence and length of coexisting strictures, bowel wall thickness, CDMI score, upstream dilation, and bowel distension. Clinical outcome was assessed using medical records. For metric data, means and standard deviation, as well as one-way ANOVA and Pearson's correlation coefficient, were calculated.

Results: In 36/642 patients with CD undergoing MRE, 49 sinus tracts (forty in small intestine, nine in left-sided colon) were detected with a prevalence of 6.9% in patients with MR-visible signs of CD (n = 519, overall prevalence of 5.6%). Mean segmental bowel wall thickness was 8.9 mm, and mean CDMI score was 9.3. All sinus tracts were located within a stenotic segment, showing mesenteric orientation within the small bowel and upstream dilation in 13 patients. Of 36 patients, 19 underwent immediate surgery and seven developed clinical progression within the segment containing the sinus tract.

Conclusions: Sinus tracts occur in 6.9% of patients with visible signs of CD. They are located within stenotic, severely thickened bowel segments with high MR inflammation scores. Their detection is clinically important, because they indicate a more aggressive phenotype and, if left untreated, may show severe progression.

Key Points: • Sinus tracts occur in 6.9% of patients with MR-visible signs of Crohn's disease. • Sinus tracts are a radiological indicator of early penetrating Crohn's disease, with a high risk of progression, and require dedicated treatment. • Sinus tracts can be recognized by characteristic findings and typically occur in stenotic, severely thickened bowel segments with high MR inflammation scores.
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http://dx.doi.org/10.1007/s00330-020-06935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476978PMC
October 2020

Reading Fast, Reading Slow: The Effect of Interviewers' Speed in Reading Introductory Texts on Response Behavior.

J Surv Stat Methodol 2020 Apr 21;8(2):325-351. Epub 2019 Mar 21.

Technical University of Munich (Chair for the Economics of Aging), Munich Center for the Economics of Aging (MEA), Max Planck Institute for Social Law and Social Policy, Amalienstr. 33, 80799 Munich, Germany.

Guidelines for interviewers frequently include instructions to read question texts exactly as they are worded. Deviations from these guidelines on standardized interviewing might affect the comparability of survey answers and impair the quality of data. This paper contributes to the literature on interviewer behavior by analyzing how interviewers change their reading behavior during fieldwork and whether this behavioral change influences the response behavior of survey respondents. We use item-level paradata from the Survey of Health, Ageing and Retirement in Europe (SHARE) to measure interviewers' reading times and focus our analyses on introductory questions that do not require an immediate response by the respondent. In contrast to prior research, this focus enables us to disentangle the reading times of interviewers from the response times of respondents. Based on fixed effects regression, our results show systematic changes in interviewers' reading times of introductory items: First, reading times significantly decrease over the survey's field period, even after controlling for relevant respondent characteristics and specific aspects of the interview situation. Second, a cross-national comparison, including fourteen European countries plus Israel, reveals that the decrease is uniform in almost all countries, suggesting its generalizability across different cultural contexts. Third, the decrease in reading times influences response behavior to varying degrees. Response behavior is affected if introductions contain relevant information for understanding or fulfilling the required task and especially if the response refers to within-survey requests. On the basis of these findings, we discuss the possible consequences for questionnaire design, interviewer training, and fieldwork monitoring.
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http://dx.doi.org/10.1093/jssam/smy027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147818PMC
April 2020

Sixth Immunotherapy of Cancer conference (ITOC): advances and perspectives-a meeting report.

J Immunother Cancer 2020 02;8(1)

Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Klinikum der Ludwig-Maximilians-Universitat Munchen, Munich, Germany

Immunotherapy has moved to the forefront of cancer treatment, illustrated by the accelerating pace of novel therapy approvals. In this complex environment, scientists rely on cutting edge conferences to stay informed. The Immunotherapy of Cancer (ITOC) conference was established jointly with the Society of the Immunotherapy of Cancer to bring the European researchers together. In its sixth edition, the ITOC conference has recently been held in Vienna, Austria.
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http://dx.doi.org/10.1136/jitc-2019-000268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057436PMC
February 2020

Direct EPR detection of atomic nitrogen in an atmospheric nitrogen plasma jet.

Phys Chem Chem Phys 2020 Feb 11;22(7):3875-3882. Epub 2020 Feb 11.

Institute of Physical Chemistry, Albert-Ludwigs-University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany.

In this study, an atmospheric nitrogen plasma jet generated by a custom-built micro-plasma device was analyzed at room temperature by continuous wave and pulse EPR spectroscopy in real time. Transiently formed nitrogen atoms were detected without the necessity to use spin-traps or other reagents for their stabilization. In contrast to results from optical emission spectroscopy, only signals from the S ground state of N and N could be detected. EPR data analysis revealed an isotropic g value of 1.9971 and isotropic hyperfine coupling constants of a(N) = (10.47 ± 0.02) MHz and a(N) = (14.69 ± 0.02) MHz. Moreover, lifetime and relaxation data could be determined; both are discussed in terms of spectral widths and actual concentrations of the transiently formed nitrogen species within the plasma jet. The data show that the lifetimes of atomic nitrogen and charged particles such as N must be different, and for the latter below the observation time window of EPR spectroscopy. We demonstrate that the real-time (pulsed) EPR technique is a fast and reliable alternative to detect atomic nitrogen in atmospheric pressure plasma jets. The method may be used for a continuous monitoring of the quality of plasma jets.
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http://dx.doi.org/10.1039/c9cp05799dDOI Listing
February 2020

Enhanced Protein Immobilization on Polymers-A Plasma Surface Activation Study.

Polymers (Basel) 2020 Jan 4;12(1). Epub 2020 Jan 4.

Laboratory for Sensors, Department of Microsystems Engineering, University of Freiburg, 79110 Freiburg, Germany.

Over the last years, polymers have gained great attention as substrate material, because of the possibility to produce low-cost sensors in a high-throughput manner or for rapid prototyping and the wide variety of polymeric materials available with different features (like transparency, flexibility, stretchability, etc.). For almost all biosensing applications, the interaction between biomolecules (for example, antibodies, proteins or enzymes) and the employed substrate surface is highly important. In order to realize an effective biomolecule immobilization on polymers, different surface activation techniques, including chemical and physical methods, exist. Among them, plasma treatment offers an easy, fast and effective activation of the surfaces by micro/nanotexturing and generating functional groups (including carboxylic acids, amines, esters, aldehydes or hydroxyl groups). Hence, here we present a systematic and comprehensive plasma activation study of various polymeric surfaces by optimizing different parameters, including power, time, substrate temperature and gas composition. Thereby, the highest immobilization efficiency along with a homogenous biomolecule distribution is achieved with a 5-min plasma treatment under a gas composition of 50% oxygen and nitrogen, at a power of 1000 W and a substrate temperature of 80 °C. These results are also confirmed by different surface characterization methods, including SEM, XPS and contact angle measurements.
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http://dx.doi.org/10.3390/polym12010104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023393PMC
January 2020

Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis.

J Immunother Cancer 2020 01 2;8(1). Epub 2020 Jan 2.

Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria

Background: The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.

Methods: We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.

Results: VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the "do not eat me" signal CD47 on tumor cells.

Conclusions: HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.
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http://dx.doi.org/10.1136/jitc-2019-000195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057438PMC
January 2020

Restoration of intestinal continuity after stoma formation for Crohn's disease in the era of biological therapy : A retrospective cohort study.

Wien Klin Wochenschr 2020 Jan 8;132(1-2):12-18. Epub 2020 Jan 8.

Division of General Surgery, Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: The rate of restoration of intestinal continuity after colonic resection and stoma creation in patients with Crohn's disease has not been well-documented in the era of biologics. Thus, the incidence of restoration of intestinal continuity since the introduction of biological drugs was assessed.

Methods: Consecutive patients (n = 43) who underwent colonic resection with ileostomy or colostomy formation for Crohn's disease at a single tertiary referral center between 2002 and 2014 were identified. Data from individual chart review were analyzed retrospectively. Patients were personally contacted for follow-up.

Results: Of the 43 patients 8 (18.4%) had a proctectomy leaving 35 patients (81.4%) with the rectum preserved. Of the 30 patients qualifying for final analysis restoration of bowel continuity was finally achieved in 10 patients (33.3%). Permanent stoma rates were comparable in the group of patients with and without biological therapy after surgery (64.3% vs. 60%). The median follow-up period was 7 years (range 3-15 years). Of the patients 20 suffered from perianal disease involvement (66.7%), which was associated with a higher rate of permanent stoma (n = 16/20, 80%) in contrast to patients without perianal disease (n = 4/10, 40%, p = 0.045).

Conclusion: The overall incidence of stoma formation was low for patients with Crohn's disease; however, once a stoma is created the chance of ending up with a permanent stoma is high even in the era of biologics. Despite the use of new therapeutic agents perianal disease increases the risk of a permanent stoma.
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http://dx.doi.org/10.1007/s00508-019-01586-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978468PMC
January 2020

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy.

Cancers (Basel) 2019 Dec 29;12(1). Epub 2019 Dec 29.

Department of Surgery, Division of General Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.
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http://dx.doi.org/10.3390/cancers12010079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017108PMC
December 2019

Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.

Neoplasia 2020 02 14;22(2):61-75. Epub 2019 Dec 14.

Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Comprehensive Cancer Centre, Medical University of Vienna, Austria. Electronic address:

Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT- versus in TA-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.
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http://dx.doi.org/10.1016/j.neo.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920197PMC
February 2020

Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma.

Cell 2019 Oct;179(4):829-845.e20

BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address:

The immune microenvironment of hepatocellular carcinoma (HCC) is poorly characterized. Combining two single-cell RNA sequencing technologies, we produced transcriptomes of CD45 immune cells for HCC patients from five immune-relevant sites: tumor, adjacent liver, hepatic lymph node (LN), blood, and ascites. A cluster of LAMP3 dendritic cells (DCs) appeared to be the mature form of conventional DCs and possessed the potential to migrate from tumors to LNs. LAMP3 DCs also expressed diverse immune-relevant ligands and exhibited potential to regulate multiple subtypes of lymphocytes. Of the macrophages in tumors that exhibited distinct transcriptional states, tumor-associated macrophages (TAMs) were associated with poor prognosis, and we established the inflammatory role of SLC40A1 and GPNMB in these cells. Further, myeloid and lymphoid cells in ascites were predominantly linked to tumor and blood origins, respectively. The dynamic properties of diverse CD45 cell types revealed by this study add new dimensions to the immune landscape of HCC.
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http://dx.doi.org/10.1016/j.cell.2019.10.003DOI Listing
October 2019

Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

Center of Pathobiochemistry and Genetics, Institute of Medical Genetics.

The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
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http://dx.doi.org/10.1172/jci.insight.124164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824305PMC
October 2019
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