TY - JOUR A1 - Hartrampf, Philipp E. A1 - Weinzierl, Franz-Xaver A1 - Serfling, Sebastian E. A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Seitz, Anna Katharina A1 - Kübler, Hubert A1 - Buck, Andreas K. A1 - Werner, Rudolf A. T1 - Hematotoxicity and nephrotoxicity in prostate cancer patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I&T JF - Cancers N2 - (1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent. KW - PSMA KW - radioligand therapy KW - RLT KW - \(^{177}\)Lu KW - nephrotoxicity KW - hematotoxicity KW - CTCAE Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254825 SN - 2072-6694 VL - 14 IS - 3 ER - TY - JOUR A1 - Kelm, Matthias A1 - Kusan, Simon A1 - Surat, Güzin A1 - Anger, Friedrich A1 - Reibetanz, Joachim A1 - Germer, Christoph-Thomas A1 - Schlegel, Nicolas A1 - Flemming, Sven T1 - Disease- and medication-specific differences of the microbial spectrum in perianal fistulizing Crohn’s Disease — relevant aspects for antibiotic therapy JF - Biomedicines N2 - Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future. KW - fistulizing Crohn’s Disease KW - microbial spectrum KW - anorectal abscess KW - perianal fistulas Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290281 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Kempf, Florian A1 - Scharnagl, Julian A1 - Heil, Stefan A1 - Schilling, Klaus T1 - Self-organizing control-loop recovery for predictive networked formation control of fractionated spacecraft JF - Aerospace N2 - Going beyond the current trend of cooperating multiple small satellites we arrive at fractionated satellite architectures. Here the subsystems of all satellites directly self-organize and cooperate among themselves to achieve a common mission goal. Although this leads to a further increase of the advantages of the initial trend it also introduces new challenges, one of which is how to perform closed-loop control of a satellite over a network of subsystems. We present a two-fold approach to deal with the two main disturbances, data losses in the network and failure of the controller, in a networked predictive formation control scenario. To deal with data loss an event based networked model predictive control approach is extended to enable it to adapt to changing network conditions. The controller failure detection and compensation approach is tailored for a possibly large network of heterogeneous cooperating actuator- and controller nodes. The self-organized control task redistribution uses an auction-based methodology. It scales well with the number of nodes and allows to optimize for continuing good control performance despite the controller switch. The stability and smooth control behavior of our approach during a self-organized controller failure compensation while also being subject to data losses was demonstrated on a hardware testbed using as mission a formation control scenario. KW - networked predictive control KW - fractionated spacecraft KW - controller failure recovery KW - self-organization KW - formation control KW - auction based task assignment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288041 SN - 2226-4310 VL - 9 IS - 10 ER - TY - JOUR A1 - Kustiati, Ulayatul A1 - Ergün, Suleyman A1 - Karnati, Srikanth A1 - Nugrahaningsih, Dwi Aris Agung A1 - Kusindarta, Dwi Liliek A1 - Wihadmadyatami, Hevi T1 - Ethanolic extract of Ocimum sanctum Linn. Inhibits cell migration of human lung adenocarcinoma cells (A549) by downregulation of integrin αvβ3, α5β1, and VEGF JF - Scientia Pharmaceutica N2 - Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF. KW - EEOS KW - A549 cell line KW - integrin α5β1 KW - integrin αvβ3 KW - VEGF Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290540 SN - 2218-0532 VL - 90 IS - 4 ER - TY - JOUR A1 - Garg, Tushar A1 - Werner, Rudolf A. A1 - Chung, Hyun Woo A1 - Khatri, Wajahat A1 - Pienta, Kenneth J. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Saad, Elie A1 - Rowe, Steven P. T1 - Association of true positivity with serum prostate-specific antigen levels and other clinical factors in indeterminate PSMA-RADS-3A lesions identified on \(^{18}\)F-DCFPyL PET/CT scans JF - Tomography N2 - The use of prostate-specific membrane antigen targeted PET imaging for the evaluation of prostate cancer has increased significantly in the last couple of decades. When evaluating these imaging findings based on the PSMA reporting and data system version 1.0, which categorize lesions based on their likelihood of prostate cancer involvement, PSMA-RADS-3A lesions are commonly seen, which are indeterminate for the presence of disease. A total of 28 patients with 171 PSMA-RADS-3A lesions on \(^{18}\)F-DCFPyL PET/CT scans from June 2016 to May 2017 who had follow-up cross-sectional imaging over time were included in this study. The PSA levels of patients with PSMA-RADS-3A lesions were categorized into four groups, 0–0.2, 0.2–1, 1–2, and >2 ng/mL. The pre-operative Gleason score of these patients was categorized into two groups, Gleason score < 7 or ≥7. The median age for these patients was 72.5 years (range 59–81). The median PSA value for patients with positive lesions was significantly higher than those with negative lesions (5.8 ng/mL vs. 0.2 ng/mL, p < 0.0001). The lesion positivity rate was significantly higher in patients with PSA > 1 ng/mL (18.2% vs. 81.9%, p < 0.001). On ROC analysis, the highest classification accuracy was seen at PSA ≥ 0.6 ng/mL of 80.12% (95% CI = 73.69–86.16%), and the area under the curve was 71.32% (95% CI = 61.9–80.7%, p < 0.0001). A total of 96.4% (108/112) of patients with positive lesions and 86.4% (51/59) of patients with negative lesions had a PSMA-RADS-4/5 lymph node on the initial \(^{18}\)F-DCFPyL PET/CT scan (p = 0.02). In patients with a Gleason score ≥ 7, the presence of positive PSMA-RADS-3A lesions was higher, compared to negative PSMA-RADS-3A lesions (p = 0.049). Higher PSA levels in patients with PSMA-RADS-3A lesions can point towards the presence of true positivity. PSA levels may be considered in deciding whether to call an indeterminate lesion on PSMA PET. KW - prostate cancer KW - prostate-specific antigen KW - PSMA-RADS KW - \(^{18}\)F-DCFPyL PET/CT KW - Gleason score Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290510 SN - 2379-139X VL - 8 IS - 6 SP - 2639 EP - 2647 ER - TY - JOUR A1 - Hutin, Stephanie A1 - Ling, Wai Li A1 - Tarbouriech, Nicolas A1 - Schoehn, Guy A1 - Grimm, Clemens A1 - Fischer, Utz A1 - Burmeister, Wim P. T1 - The vaccinia virus DNA helicase structure from combined single-particle cryo-electron microscopy and AlphaFold2 prediction JF - Viruses N2 - Poxviruses are large DNA viruses with a linear double-stranded DNA genome circularized at the extremities. The helicase-primase D5, composed of six identical 90 kDa subunits, is required for DNA replication. D5 consists of a primase fragment flexibly attached to the hexameric C-terminal polypeptide (res. 323–785) with confirmed nucleotide hydrolase and DNA-binding activity but an elusive helicase activity. We determined its structure by single-particle cryo-electron microscopy. It displays an AAA+ helicase core flanked by N- and C-terminal domains. Model building was greatly helped by the predicted structure of D5 using AlphaFold2. The 3.9 Å structure of the N-terminal domain forms a well-defined tight ring while the resolution decreases towards the C-terminus, still allowing the fit of the predicted structure. The N-terminal domain is partially present in papillomavirus E1 and polyomavirus LTA helicases, as well as in a bacteriophage NrS-1 helicase domain, which is also closely related to the AAA+ helicase domain of D5. Using the Pfam domain database, a D5_N domain followed by DUF5906 and Pox_D5 domains could be assigned to the cryo-EM structure, providing the first 3D structures for D5_N and Pox_D5 domains. The same domain organization has been identified in a family of putative helicases from large DNA viruses, bacteriophages, and selfish DNA elements. KW - DNA replication KW - helicase KW - Pfam domain KW - poxvirus KW - cryo-electron microscopy KW - structure prediction KW - SF3 helicase KW - orthopoxvirus KW - DNA helicase Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290523 SN - 1999-4915 VL - 14 IS - 10 ER - TY - JOUR A1 - Hill, Aileen A1 - Dossow, Vera von A1 - Heyland, Daren K. A1 - Rossaint, Rolf A1 - Meybohm, Patrick A1 - Fox, Henrik A1 - Morshuis, Michiel A1 - Elke, Gunnar A1 - Panholzer, Bernd A1 - Haneya, Assad A1 - Böning, Andreas A1 - Niemann, Bernd A1 - Zayat, Rashad A1 - Moza, Ajay A1 - Stoppe, Christian T1 - Preoperative nutritional optimization and physical exercise for patients scheduled for elective implantation for a left-ventricular assist device — The PROPER-LVAD study JF - Surgeries N2 - Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted. KW - prehabilitation KW - medical nutrition therapy KW - in-bed cycling KW - left-ventricular assist device KW - trial protocol KW - clinical trial KW - oral nutrition supplements Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288317 SN - 2673-4095 N1 - Funding: This investigator-initiated trial is supported by a grant from Fresenius Kabi Deutschland (Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg). The oral nutrition supplements (Fresubin PRO®) are provided by Fresenius Kabi Germany. VL - 3 IS - 4 SP - 284 EP - 296 ER - TY - JOUR A1 - Pluta, Natalie A1 - Hoffjan, Sabine A1 - Zimmer, Frederic A1 - Köhler, Cornelia A1 - Lücke, Thomas A1 - Mohr, Jennifer A1 - Vorgerd, Matthias A1 - Nguyen, Hoa Huu Phuc A1 - Atlan, David A1 - Wolf, Beat A1 - Zaum, Ann-Kathrin A1 - Rost, Simone T1 - Homozygous inversion on chromosome 13 involving SGCG detected by short read whole genome sequencing in a patient suffering from limb-girdle muscular dystrophy JF - Genes N2 - New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving SGCG and LINC00621 was detected. The breakpoint in intron 2 of SGCG led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman. KW - inversion KW - sarcoglycanopathy KW - whole genome sequencing (WGS) KW - next generation sequencing (NGS) KW - LGMDR5 KW - muscle disease KW - genetic diagnostics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288122 SN - 2073-4425 VL - 13 IS - 10 ER - TY - JOUR A1 - vom Dahl, Christian A1 - Müller, Christoph Emanuel A1 - Berisha, Xhevat A1 - Nagel, Georg A1 - Zimmer, Thomas T1 - Coupling the cardiac voltage-gated sodium channel to channelrhodopsin-2 generates novel optical switches for action potential studies JF - Membranes N2 - Voltage-gated sodium (Na\(^+\)) channels respond to short membrane depolarization with conformational changes leading to pore opening, Na\(^+\) influx, and action potential (AP) upstroke. In the present study, we coupled channelrhodopsin-2 (ChR2), the key ion channel in optogenetics, directly to the cardiac voltage-gated Na\(^+\) channel (Na\(_v\)1.5). Fusion constructs were expressed in Xenopus laevis oocytes, and electrophysiological recordings were performed by the two-microelectrode technique. Heteromeric channels retained both typical Na\(_v\)1.5 kinetics and light-sensitive ChR2 properties. Switching to the current-clamp mode and applying short blue-light pulses resulted either in subthreshold depolarization or in a rapid change of membrane polarity typically seen in APs of excitable cells. To study the effect of individual K\(^+\) channels on the AP shape, we co-expressed either K\(_v\)1.2 or hERG with one of the Na\(_v\)1.5-ChR2 fusions. As expected, both delayed rectifier K\(^+\) channels shortened AP duration significantly. K\(_v\)1.2 currents remarkably accelerated initial repolarization, whereas hERG channel activity efficiently restored the resting membrane potential. Finally, we investigated the effect of the LQT3 deletion mutant ΔKPQ on the AP shape and noticed an extremely prolonged AP duration that was directly correlated to the size of the non-inactivating Na\(^+\) current fraction. In conclusion, coupling of ChR2 to a voltage-gated Na\(^+\) channel generates optical switches that are useful for studying the effect of individual ion channels on the AP shape. Moreover, our novel optogenetic approach provides the potential for an application in pharmacology and optogenetic tissue-engineering. KW - optogenetics KW - channelrhodopsin KW - voltage-gated Na\(^+\) channel KW - action potential KW - delayed rectifier potassium channel KW - hERG KW - long QT syndrome Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288228 SN - 2077-0375 VL - 12 IS - 10 ER - TY - JOUR A1 - Just, Janina A1 - Siller, Hans-Stefan T1 - The role of mathematics in STEM secondary classrooms: a systematic literature review JF - Education Sciences N2 - Nowadays, science, technology, engineering, and mathematics (STEM) play a critical role in a nation’s global competitiveness and prosperity. Thus, there is a need to educate students in these subjects to meet the current and future demands of personal life and society. While applications, especially in science, engineering, and technology, are directly obvious, mathematics underpins the other STEM disciplines. It is recognized that mathematics is the foundation for all other STEM disciplines; the role of mathematics in classrooms is not clear yet. Therefore, the question arises: What is the current role of mathematics in secondary STEM classrooms? To answer this question, we conducted a systematic literature review based on three publication databases (Web of Science, ERIC, and EBSCO Teacher Referral Center). This literature review paper is intended to contribute to the current state of the role of mathematics in STEM education in secondary classrooms. Through the search, starting with 1910 documents, only 14 eligible documents were found. In these, mathematics is often seen as a minor matter and a means to an end in the eyes of science educators. From this, we conclude that the role of mathematics in the STEM classroom should be further strengthened. Overall, the paper highlights a major research gap, and proposes possible initial solutions to close it. KW - STEM education KW - role of mathematics in STEM KW - literature review KW - STEM integration KW - STEM classroom KW - secondary education Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288075 SN - 2227-7102 VL - 12 IS - 9 ER - TY - JOUR A1 - Steinmann, Rebekka A1 - Cortegoso Valdivia, Pablo A1 - Nowak, Tanja A1 - Koulaouzidis, Anastasios T1 - An overview of the evolution of capsule endoscopy research — text-mining analysis and publication trends JF - Diagnostics N2 - There has been a steady increase (annual percentage growth rate of 19.2%, average of 18.3 citations per document) in capsule endoscopy (CE) publications from a global, interdisciplinary research community on a growing range of CE applications over the last 20+ years. We here present the status of CE as a field of research, tracing its evolution over time and providing insight into its potential for diagnostics, prevention and treatment of gastrointestinal (GI) tract diseases. To portray the development of the CE research landscape in the 2000–2021 time span, we analyzed 5764 scientific publications. Analyses were performed using the R language and environment for statistical computing and graphics and VOSviewer, a software developed for scientific literature analysis by scientometricians. The aim of this paper is to provide a wide comprehensive analysis of the trends in CE publications. We thus performed subgroup analysis on the selected papers, including indications, annual percentage growth rate, average citations per document, most publications from research areas/interdisciplinary field of the articles, geography, collaboration networks through institutions, specific clinical keywords and device type. The firm increase in CE publications over the last two decades highlights the overall strength of the technology in GI applications. Furthermore, the introduction to the field of artificial intelligence (AI) tools has been promoting a range of technological advances that keep on affecting the diagnostic potential of CE. KW - capsule endoscopy KW - research KW - meta-view Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288515 SN - 2075-4418 VL - 12 IS - 9 ER - TY - JOUR A1 - Seethaler, Marius A1 - Hertlein, Tobias A1 - Hopke, Elisa A1 - Köhling, Paul A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel effective fluorinated benzothiophene-indole hybrid antibacterials against S. aureus and MRSA strains JF - Pharmaceuticals N2 - Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds. KW - antibacterial drug resistance KW - structure activity KW - synthesis KW - inhibition KW - substituent Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288253 SN - 1424-8247 VL - 15 IS - 9 ER - TY - JOUR A1 - Schlund, Jonas A1 - German, Reinhard A1 - Pruckner, Marco T1 - Synergy of unidirectional and bidirectional smart charging of electric vehicles for frequency containment reserve power provision JF - World Electric Vehicle Journal N2 - Besides the integration of renewable energies, electric vehicles pose an additional challenge to modern power grids. However, electric vehicles can also be a flexibility source and contribute to the power system stability. Today, the power system still heavily relies on conventional technologies to stay stable. In order to operate a future power system based on renewable energies only, we need to understand the flexibility potential of assets such as electric vehicles and become able to use their flexibility. In this paper, we analyzed how vast amounts of coordinated charging processes can be used to provide frequency containment reserve power, one of the most important ancillary services for system stability. Therefore, we used an extensive simulation model of a virtual power plant of millions of electric vehicles. The model considers not only technical components but also the stochastic behavior of electric vehicle drivers based on real data. Our results show that, in 2030, electric vehicles have the potential to serve the whole frequency containment reserve power market in Germany. We differentiate between using unidirectional and bidirectional chargers. Bidirectional chargers have a larger potential but also result in unwanted battery degradation. Unidirectional chargers are more constrained in terms of flexibility, but do not lead to additional battery degradation. We conclude that using a mix of both can combine the advantages of both worlds. Thereby, average private cars can provide the service without any notable additional battery degradation and achieve yearly earnings between EUR 200 and EUR 500, depending on the volatile market prices. Commercial vehicles have an even higher potential, as the results increase with vehicle utilization and consumption. KW - smart charging KW - electric vehicles KW - simulation KW - ancillary services KW - smart grid Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288324 SN - 2032-6653 VL - 13 IS - 9 ER - TY - JOUR A1 - Nyawale, Helmut A. A1 - Moremi, Nyambura A1 - Mohamed, Mohamed A1 - Njwalila, Johnson A1 - Silago, Vitus A1 - Krone, Manuel A1 - Konje, Eveline T. A1 - Mirambo, Mariam M. A1 - Mshana, Stephen E. T1 - High seroprevalence of SARS-CoV-2 in Mwanza, northwestern Tanzania: a population-based survey JF - International Journal of Environmental Research and Public Health N2 - The transmission of the SARS-CoV-2 virus, which causes COVID-19, has been documented worldwide. However, the evidence of the extent to which transmission has occurred in different countries is still to be established. Understanding the magnitude and distribution of SARS-CoV-2 through seroprevalence studies is important in designing control and preventive strategies in communities. This study investigated the seropositivity of the SARS-CoV-2 virus antibodies in the communities of three different districts in the Mwanza region, Tanzania. A household cross-sectional survey was conducted in September 2021 using the modified African Centre for Disease and Prevention (ACDC) survey protocol. A blood sample was obtained from one member of each of the selected households who consented to take part in the survey. Immunochromatographic rapid test kits were used to detect IgM and IgG SARS-CoV-2 antibodies, followed by descriptive data analysis. Overall, 805 participants were enrolled in the study with a median age of 35 (interquartile range (IQR):27–47) years. The overall SARS-CoV-2 seropositivity was 50.4% (95%CI: 46.9–53.8%). The IgG and IgM seropositivity of the SARS-CoV-2 antibodies was 49.3% and 7.2%, respectively, with 6.1% being both IgG and IgM seropositive. A history of runny nose (aOR: 1.84, 95%CI: 1.03–3.5, p = 0.036), loss of taste (aOR: 1.84, 95%CI: 1.12–4.48, p = 0.023), and living in Ukerewe (aOR: 3.55, 95%CI: 1.68–7.47, p = 0.001) and Magu (aOR: 2.89, 95%CI: 1.34–6.25, p= 0.007) were all independently associated with SARS-CoV-2 IgM seropositivity. Out of the studied factors, living in the Ukerewe district was independently associated with IgG seropositivity (aOR 1.29, CI 1.08–1.54, p = 0.004). Twenty months after the first case of COVID-19 in Tanzania, about half of the studied population in Mwanza was seropositive for SARS-CoV-2. KW - SARS-CoV-2 KW - COVID-19 KW - seroprevalence KW - antibodies KW - Mwanza KW - Tanzania Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288134 SN - 1660-4601 VL - 19 IS - 18 ER - TY - JOUR A1 - Tanoey, Justine A1 - Baechle, Christina A1 - Brenner, Hermann A1 - Deckert, Andreas A1 - Fricke, Julia A1 - Günther, Kathrin A1 - Karch, André A1 - Keil, Thomas A1 - Kluttig, Alexander A1 - Leitzmann, Michael A1 - Mikolajczyk, Rafael A1 - Obi, Nadia A1 - Pischon, Tobias A1 - Schikowski, Tamara A1 - Schipf, Sabine M. A1 - Schulze, Matthias B. A1 - Sedlmeier, Anja A1 - Moreno Velásquez, Ilais A1 - Weber, Katharina S. A1 - Völzke, Henry A1 - Ahrens, Wolfgang A1 - Gastell, Sylvia A1 - Holleczek, Bernd A1 - Jöckel, Karl-Heinz A1 - Katzke, Verena A1 - Lieb, Wolfgang A1 - Michels, Karin B. A1 - Schmidt, Börge A1 - Teismann, Henning A1 - Becher, Heiko T1 - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort JF - International Journal of Environmental Research and Public Health N2 - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection. KW - perinatal KW - adult-onset KW - late-onset KW - autoimmune KW - delivery mode KW - sex KW - offspring KW - NAKO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216 SN - 1660-4601 VL - 19 IS - 17 ER - TY - JOUR A1 - Schaffarczyk, Alois A1 - Koehn, Silas A1 - Oggiano, Luca A1 - Schaffarczyk, Kai T1 - Aerodynamic benefits by optimizing cycling posture JF - Applied Sciences N2 - An approach to aerodynamically optimizing cycling posture and reducing drag in an Ironman (IM) event was elaborated. Therefore, four commonly used positions in cycling were investigated and simulated for a flow velocity of 10 m/s and yaw angles of 0–20° using OpenFoam-based Nabla Flow CFD simulation software software. A cyclist was scanned using an IPhone 12, and a special-purpose meshing software BLENDER was used. Significant differences were observed by changing and optimizing the cyclist’s posture. Aerodynamic drag coefficient (CdA) varies by more than a factor of 2, ranging from 0.214 to 0.450. Within a position, the CdA tends to increase slightly at yaw angles of 5–10° and decrease at higher yaw angles compared to a straight head wind, except for the time trial (TT) position. The results were applied to the IM Hawaii bike course (180 km), estimating a constant power output of 300 W. Including the wind distributions, two different bike split models for performance prediction were applied. Significant time saving of roughly 1 h was found. Finally, a machine learning approach to deduce 3D triangulation for specific body shapes from 2D pictures was tested. KW - aerodynamic drag reduction KW - cycling KW - machine learning KW - drag area Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285942 SN - 2076-3417 VL - 12 IS - 17 ER - TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Floren, Andreas A1 - Linsenmair, Karl Eduard A1 - Müller, Tobias T1 - Diversity and functional relevance of canopy arthropods in Central Europe JF - Diversity N2 - Although much is known about the ecology and functional importance of canopy arthropods in temperate forests, few studies have tried to assess the overall diversity and investigate the composition and dynamics of tree-specific communities. This has impeded a deeper understanding of the functioning of forests, and of how to maintain system services. Here, we present the first comprehensive data of whole arthropod communities, collected by insecticidal knockdown (fogging) from 1159 trees in 18 study areas in Central Europe during the last 25 years. The data includes 3,253,591 arthropods from 32 taxa (order, suborder, family) collected on 24 tree species from 18 genera. Fogging collects free-living, ectophytic arthropods in approximately the same number as they occur in the trees. To our knowledge, these are the most comprehensive data available today on the taxonomic composition of arboreal fauna. Assigning all arthropods to their feeding guild provided a proxy of their functional importance. The data showed that the canopy communities were regularly structured, with a clear dominance hierarchy comprised of eight ‘major taxa’ that represented 87% of all arthropods. Despite significant differences in the proportions of taxa on deciduous and coniferous trees, the composition of the guilds was very similar. The individual tree genera, on the other hand, showed significant differences in guild composition, especially when different study areas and years were compared, whereas tree-specific traits, such as tree height, girth in breast height or leaf cover, explained little of the overall variance. On the ordinal level, guild composition also differed significantly between managed and primary forests, with a simultaneous low within-group variability, indicating that management is a key factor determining the distribution of biodiversity and guild composition. KW - temperate forests KW - insecticidal knockdown KW - community structure KW - functional diversity KW - guild constancy KW - forest management KW - pristine forests KW - Bialowieza Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285924 SN - 1424-2818 VL - 14 IS - 8 ER - TY - JOUR A1 - Thal, Serge C. A1 - Smetak, Manuel A1 - Hayashi, Kentaro A1 - Förster, Carola Y. T1 - Hemorrhagic cerebral insults and secondary Takotsubo syndrome: findings in a novel in vitro model using human blood samples JF - International Journal of Molecular Sciences N2 - Intracranial hemorrhage results in devastating forms of cerebral damage. Frequently, these results also present with cardiac dysfunction ranging from ECG changes to Takotsubo syndrome (TTS). This suggests that intracranial bleeding due to subarachnoid hemorrhage (SAH) disrupts the neuro–cardiac axis leading to neurogenic stress cardiomyopathy (NSC) of different degrees. Following this notion, SAH and secondary TTS could be directly linked, thus contributing to poor outcomes. We set out to test if blood circulation is the driver of the brain–heart axis by investigating serum samples of TTS patients. We present a novel in vitro model combining SAH and secondary TTS to mimic the effects of blood or serum, respectively, on blood–brain barrier (BBB) integrity using in vitro monolayers of an established murine model. We consistently demonstrated decreased monolayer integrity and confirmed reduced Claudin-5 and Occludin levels by RT-qPCR and Western blot and morphological reorganization of actin filaments in endothelial cells. Both tight junction proteins show a time-dependent reduction. Our findings highlight a faster and more prominent disintegration of BBB in the presence of TTS and support the importance of the bloodstream as a causal link between intracerebral bleeding and cardiac dysfunction. This may represent potential targets for future therapeutic inventions in SAH and TTS. KW - Takotsubo syndrome KW - subarachnoid hemorrhage KW - inflammation KW - in vitro KW - blood KW - blood–brain barrier KW - human KW - patient KW - endothelial cells Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288305 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Kraft, Peter A1 - Schuhmann, Michael K. T1 - Cellular and molecular targets in acute ischemic stroke JF - International Journal of Molecular Sciences N2 - No abstract available Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288294 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Greite, Robert A1 - Störmer, Johanna A1 - Gueler, Faikah A1 - Khalikov, Rasul A1 - Haverich, Axel A1 - Kühn, Christian A1 - Madrahimov, Nodir A1 - Natanov, Ruslan T1 - Different acute kidney injury patterns after renal ischemia reperfusion injury and extracorporeal membrane oxygenation in mice JF - International Journal of Molecular Sciences N2 - The use of extracorporeal membrane oxygenation (ECMO) is associated with acute kidney injury (AKI) in thoracic organ transplantation. However, multiple other factors contribute to AKI development after these procedures such as renal ischemia-reperfusion injury (IRI) due to hypo-perfusion of the kidney during surgery. In this study, we aimed to explore the kidney injury patterns in mouse models of ECMO and renal IRI. Kidneys of C57BL/6 mice were examined after moderate (35 min) and severe (45 min) unilateral transient renal pedicle clamping and 2 h of veno-venous ECMO. Renal injury markers, neutrophil infiltration, tubular transport function, pro-inflammatory cytokines, and renal heme oxygenase-1 (HO-1) expression were determined by immunofluorescence and qPCR. Both procedures caused AKI, but with different injury patterns. Severe neutrophil infiltration of the kidney was evident after renal IRI, but not following ECMO. Tubular transport function was severely impaired after renal IRI, but preserved in the ECMO group. Both procedures caused upregulation of pro-inflammatory cytokines in the renal tissue, but with different time kinetics. After ECMO, but not IRI, HO-1 was strongly induced in tubular cells indicating contact with hemolysis-derived proteins. After IRI, HO-1 was expressed on infiltrating myeloid cells in the tubulo-interstitial space. In conclusion, renal IRI and ECMO both caused AKI, but kidney damage after renal IRI was more pronounced including severe neutrophil infiltration and tubular transport impairment. Enhanced HO-1 expression in tubular cells after ECMO encourages limitation of hemolysis as a therapeutic approach to reduce ECMO-associated AKI. KW - acute kidney injury KW - extracorporeal membrane oxygenation KW - heme oxygenase-1 KW - renal inflammation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288282 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Gmach, Philipp A1 - Bathe-Peters, Marc A1 - Telugu, Narasimha A1 - Miller, Duncan C. A1 - Annibale, Paolo T1 - Fluorescence spectroscopy of low-level endogenous β-adrenergic receptor expression at the plasma membrane of differentiating human iPSC-derived cardiomyocytes JF - International Journal of Molecular Sciences N2 - The potential of human-induced pluripotent stem cells (hiPSCs) to be differentiated into cardiomyocytes (CMs) mimicking adult CMs functional morphology, marker genes and signaling characteristics has been investigated since over a decade. The evolution of the membrane localization of CM-specific G protein-coupled receptors throughout differentiation has received, however, only limited attention to date. We employ here advanced fluorescent spectroscopy, namely linescan Fluorescence Correlation Spectroscopy (FCS), to observe how the plasma membrane abundance of the β\(_1\)- and β\(_2\)-adrenergic receptors (β\(_{1/2}\)-ARs), labelled using a bright and photostable fluorescent antagonist, evolves during the long-term monolayer culture of hiPSC-derived CMs. We compare it to the kinetics of observed mRNA levels in wildtype (WT) hiPSCs and in two CRISPR/Cas9 knock-in clones. We conduct these observations against the backdrop of our recent report of cell-to-cell expression variability, as well as of the subcellular localization heterogeneity of β-ARs in adult CMs. KW - GPCR KW - β-adrenergic receptors KW - hiPSC-CM KW - cardiomyocyte KW - fluorescence correlation spectroscopy KW - FCS KW - fluorescence KW - CRISPR/Cas9 KW - differentiation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288277 SN - 1422-0067 VL - 23 IS - 18 ER - TY - JOUR A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Bellut, Maximilian A1 - Stegner, David A1 - Heinze, Katrin G. A1 - Pham, Mirko A1 - Nieswandt, Bernhard A1 - Stoll, Guido T1 - Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion JF - International Journal of Molecular Sciences N2 - During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte–platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα–von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia–reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke. KW - ischemic penumbra KW - Orai2 KW - glycoprotein receptor Ibα KW - ischemic stroke KW - thrombo-inflammation KW - middle cerebral artery occlusion Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286038 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Fischer, Dania A1 - Thies, Fabian A1 - Awad, Omar A1 - Brat, Camilla A1 - Meybohm, Patrick A1 - Baer, Patrick C. A1 - Müller, Markus M. A1 - Urbschat, Anja A1 - Maier, Thorsten J. A1 - Zacharowski, Kai A1 - Roos, Jessica T1 - Red blood cell-derived microparticles exert no cancer promoting effects on colorectal cancer cells in vitro JF - International Journal of Molecular Sciences N2 - The biomedical consequences of allogeneic blood transfusions and the possible pathomechanisms of transfusion-related morbidity and mortality are still not entirely understood. In retrospective studies, allogeneic transfusion was associated with increased rates of cancer recurrence, metastasis and death in patients with colorectal cancer. However, correlation does not imply causation. The purpose of this study was to elucidate this empirical observation further in order to address insecurity among patients and clinicians. We focused on the in vitro effect of microparticles derived from red blood cell units (RMPs). We incubated different colon carcinoma cells with RMPs and analyzed their effects on growth, invasion, migration and tumor marker expression. Furthermore, effects on Wnt, Akt and ERK signaling were explored. Our results show RMPs do not seem to affect functional and phenotypic characteristics of different colon carcinoma cells and did not induce or inhibit Wnt, Akt or ERK signaling, albeit in cell culture models lacking tumor microenvironment. Allogeneic blood transfusions are associated with poor prognosis, but RMPs do not seem to convey tumor-enhancing effects. Most likely, the circumstances that necessitate the transfusion, such as preoperative anemia, tumor stage, perioperative blood loss and extension of surgery, take center stage. KW - transfusion KW - red blood cells KW - microparticles KW - colorectal carcinoma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286018 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Djelić, Ninoslav A1 - Borozan, Sunčica A1 - Dimitrijević-Srećković, Vesna A1 - Pajović, Nevena A1 - Mirilović, Milorad A1 - Stopper, Helga A1 - Stanimirović, Zoran T1 - Oxidative stress and DNA damage in peripheral blood mononuclear cells from normal, obese, prediabetic and diabetic persons exposed to thyroid hormone in vitro JF - International Journal of Molecular Sciences N2 - Diabetes, a chronic group of medical disorders characterized byhyperglycemia, has become a global pandemic. Some hormones may influence the course and outcome of diabetes, especially if they potentiate the formation of reactive oxygen species (ROS). There is a close relationship between thyroid disorders and diabetes. The main objective of this investigation was to find out whether peripheral blood mononuclear cells (PBMCs) are more prone to DNA damage by triiodothyronine (T\(_3\)) (0.1, 1 and 10 μM) at various stages of progression through diabetes (obese, prediabetics, and type 2 diabetes mellitus—T2DM persons). In addition, some biochemical parameters of oxidative stress (catalase-CAT, thiobarbituric acid reactive substances—TBARS) and lactate dehydrogenase (LDH) were evaluated. PBMCs from prediabetic and diabetic patients exhibited increased sensitivity for T\(_3\) regarding elevated level of DNA damage, inhibition of catalase, and increase of TBARS and LDH. PBMCs from obese patients reacted in the same manner, except for DNA damage. The results of this study should contribute to a better understanding of the role of thyroid hormones in the progression of T2DM. KW - diabetes KW - oxidative stress KW - DNA damage KW - lymphocytes KW - thyroid hormone Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285988 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Nagai, Michiaki A1 - Ergün, Süleyman A1 - Braunger, Barbara M. A1 - Förster, Carola Y. T1 - The protective effects of neurotrophins and microRNA in diabetic retinopathy, nephropathy and heart failure via regulating endothelial function JF - Biomolecules N2 - Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted. KW - diabetic retinopathy KW - diabetes mellitus KW - microvascular complications KW - diabetic nephropathy KW - heart failure KW - microRNA KW - neurotrophins Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285966 SN - 2218-273X VL - 12 IS - 8 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Kessler, Almuth F. A1 - Domröse, Dominik A1 - Hörmann, Julia A1 - Schaeffer, Clara A1 - Giniunaite, Aiste A1 - Burek, Malgorzata A1 - Tempel-Brami, Catherine A1 - Voloshin, Tali A1 - Volodin, Alexandra A1 - Zeidan, Adel A1 - Giladi, Moshe A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Förster, Carola Y. A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) reversibly permeabilize the blood–brain barrier in vitro and in vivo JF - Biomolecules N2 - Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. KW - blood–brain barrier KW - TTFields KW - CNS disorders Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288057 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Nazzal, Yousef A1 - Howari, Fares M. A1 - Yaslam, Aya A1 - Iqbal, Jibran A1 - Maloukh, Lina A1 - Ambika, Lakshmi Kesari A1 - Al-Taani, Ahmed A. A1 - Ali, Ijaz A1 - Othman, Eman M. A1 - Jamal, Arshad A1 - Naseem, Muhammad T1 - A methodological review of tools that assess dust microbiomes, metatranscriptomes and the particulate chemistry of indoor dust JF - Atmosphere N2 - Indoor house dust is a blend of organic and inorganic materials, upon which diverse microbial communities such as viruses, bacteria and fungi reside. Adequate moisture in the indoor environment helps microbial communities multiply fast. The outdoor air and materials that are brought into the buildings by airflow, sandstorms, animals pets and house occupants endow the indoor dust particles with extra features that impact human health. Assessment of the health effects of indoor dust particles, the type of indoor microbial inoculants and the secreted enzymes by indoor insects as allergens merit detailed investigation. Here, we discuss the applications of next generation sequencing (NGS) technology which is used to assess microbial diversity and abundance of the indoor dust environments. Likewise, the applications of NGS are discussed to monitor the gene expression profiles of indoor human occupants or their surrogate cellular models when exposed to aqueous solution of collected indoor dust samples. We also highlight the detection methods of dust allergens and analytical procedures that quantify the chemical nature of indoor particulate matter with a potential impact on human health. Our review is thus unique in advocating the applications of interdisciplinary approaches that comprehensively assess the health effects due to bad air quality in built environments. KW - indoor dust KW - allergens KW - metagenomics KW - particulate matter KW - microbiomes KW - transcriptomes KW - health effects Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285957 SN - 2073-4433 VL - 13 IS - 8 ER - TY - JOUR A1 - Wildervanck, Martijn J. A1 - Hecht, Reinhard A1 - Nowak-Król, Agnieszka T1 - Synthesis and strong solvatochromism of push-pull thienylthiazole boron complexes JF - Molecules N2 - The solvatochromic behavior of two donor-π bridge-acceptor (D-π-A) compounds based on the 2-(3-boryl-2-thienyl)thiazole π-linker and indandione acceptor moiety are investigated. DFT/TD-DFT calculations were performed in combination with steady-state absorption and emission measurements, along with electrochemical studies, to elucidate the effect of two different strongly electron-donating hydrazonyl units on the solvatochromic and fluorescence behavior of these compounds. The Lippert–Mataga equation was used to estimate the change in dipole moments (Δµ) between ground and excited states based on the measured spectroscopic properties in solvents of varying polarity with the data being supported by theoretical studies. The two asymmetrical D-π-A molecules feature strong solvatochromic shifts in fluorescence of up to ~4300 cm\(^{−1}\) and a concomitant change of the emission color from yellow to red. These changes were accompanied by an increase in Stokes shift to reach values as large as ~5700–5800 cm\(^{−1}\). Quantum yields of ca. 0.75 could be observed for the N,N-dimethylhydrazonyl derivative in nonpolar solvents, which gradually decreased along with increasing solvent polarity, as opposed to the consistently reduced values obtained for the N,N-diphenylhydrazonyl derivative of up to ca. 0.20 in nonpolar solvents. These two push–pull molecules are contrasted with a structurally similar acceptor-π bridge-acceptor (A-π-A) compound. KW - solvatochromism KW - donor–acceptor KW - fluorescence KW - hydrazone KW - Lippert–Mataga plot KW - push–pull thienylthiazole KW - tetracoordinated boron Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286186 SN - 1420-3049 VL - 27 IS - 17 ER - TY - JOUR A1 - Masota, Nelson E. A1 - Ohlsen, Knut A1 - Schollmayer, Curd A1 - Meinel, Lorenz A1 - Holzgrabe, Ulrike T1 - Isolation and characterization of galloylglucoses effective against multidrug-resistant strains of Escherichia coli and Klebsiella pneumoniae JF - Molecules N2 - The search for new antibiotics against multidrug-resistant (MDR), Gram-negative bacteria is crucial with respect to filling the antibiotics development pipeline, which is subject to a critical shortage of novel molecules. Screening of natural products is a promising approach for identifying antimicrobial compounds hosting a higher degree of novelty. Here, we report the isolation and characterization of four galloylglucoses active against different MDR strains of Escherichia coli and Klebsiella pneumoniae. A crude acetone extract was prepared from Paeonia officinalis Linnaeus leaves, and bioautography-guided isolation of active compounds from the extract was performed by liquid–liquid extraction, as well as open column, flash, and preparative chromatographic methods. Isolated active compounds were characterized and elucidated by a combination of spectroscopic and spectrometric techniques. In vitro antimicrobial susceptibility testing was carried out on E. coli and K. pneumoniae using 2 reference strains and 13 strains hosting a wide range of MDR phenotypes. Furthermore, in vivo antibacterial activities were assessed using Galleria mellonella larvae, and compounds 1,2,3,4,6-penta-O-galloyl-β-d-glucose, 3-O-digalloyl-1,2,4,6-tetra-O-galloyl-β-d-glucose, 6-O-digalloyl-1,2,3,4-tetra-O-galloyl-β-d-glucose, and 3,6-bis-O-digalloyl-1,2,4-tri-O-galloyl-β-d-glucose were isolated and characterized. They showed minimum inhibitory concentration (MIC) values in the range of 2–256 µg/mL across tested bacterial strains. These findings have added to the number of known galloylglucoses from P. officinalis and highlight their potential against MDR Gram-negative bacteria. KW - antimicrobial resistance KW - Enterobacteriaceae KW - Paeonia KW - gallotannins KW - isolation KW - structural elucidation KW - Escherichia coli KW - Klebsiella pneumoniae Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286179 SN - 1420-3049 VL - 27 IS - 15 ER - TY - JOUR A1 - Kacic, Patrick A1 - Kuenzer, Claudia T1 - Forest biodiversity monitoring based on remotely sensed spectral diversity — a review JF - Remote Sensing N2 - Forests are essential for global environmental well-being because of their rich provision of ecosystem services and regulating factors. Global forests are under increasing pressure from climate change, resource extraction, and anthropologically-driven disturbances. The results are dramatic losses of habitats accompanied with the reduction of species diversity. There is the urgent need for forest biodiversity monitoring comprising analysis on α, β, and γ scale to identify hotspots of biodiversity. Remote sensing enables large-scale monitoring at multiple spatial and temporal resolutions. Concepts of remotely sensed spectral diversity have been identified as promising methodologies for the consistent and multi-temporal analysis of forest biodiversity. This review provides a first time focus on the three spectral diversity concepts “vegetation indices”, “spectral information content”, and “spectral species” for forest biodiversity monitoring based on airborne and spaceborne remote sensing. In addition, the reviewed articles are analyzed regarding the spatiotemporal distribution, remote sensing sensors, temporal scales and thematic foci. We identify multispectral sensors as primary data source which underlines the focus on optical diversity as a proxy for forest biodiversity. Moreover, there is a general conceptual focus on the analysis of spectral information content. In recent years, the spectral species concept has raised attention and has been applied to Sentinel-2 and MODIS data for the analysis from local spectral species to global spectral communities. Novel remote sensing processing capacities and the provision of complementary remote sensing data sets offer great potentials for large-scale biodiversity monitoring in the future. KW - forest KW - biodiversity KW - alpha diversity KW - beta diversity KW - gamma diversity KW - spectral variation hypothesis KW - spectral diversity KW - optical diversity KW - satellite data KW - remote sensing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290535 SN - 2072-4292 VL - 14 IS - 21 ER - TY - JOUR A1 - Koehler, Jonas A1 - Bauer, André A1 - Dietz, Andreas J. A1 - Kuenzer, Claudia T1 - Towards forecasting future snow cover dynamics in the European Alps — the potential of long optical remote-sensing time series JF - Remote Sensing N2 - Snow is a vital environmental parameter and dynamically responsive to climate change, particularly in mountainous regions. Snow cover can be monitored at variable spatial scales using Earth Observation (EO) data. Long-lasting remote sensing missions enable the generation of multi-decadal time series and thus the detection of long-term trends. However, there have been few attempts to use these to model future snow cover dynamics. In this study, we, therefore, explore the potential of such time series to forecast the Snow Line Elevation (SLE) in the European Alps. We generate monthly SLE time series from the entire Landsat archive (1985–2021) in 43 Alpine catchments. Positive long-term SLE change rates are detected, with the highest rates (5–8 m/y) in the Western and Central Alps. We utilize this SLE dataset to implement and evaluate seven uni-variate time series modeling and forecasting approaches. The best results were achieved by Random Forests, with a Nash–Sutcliffe efficiency (NSE) of 0.79 and a Mean Absolute Error (MAE) of 258 m, Telescope (0.76, 268 m), and seasonal ARIMA (0.75, 270 m). Since the model performance varies strongly with the input data, we developed a combined forecast based on the best-performing methods in each catchment. This approach was then used to forecast the SLE for the years 2022–2029. In the majority of the catchments, the shift of the forecast median SLE level retained the sign of the long-term trend. In cases where a deviating SLE dynamic is forecast, a discussion based on the unique properties of the catchment and past SLE dynamics is required. In the future, we expect major improvements in our SLE forecasting efforts by including external predictor variables in a multi-variate modeling approach. KW - forecast KW - Earth Observation KW - time series KW - Snow Line Elevation KW - Alps KW - mountains KW - environmental modeling KW - machine learning Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288338 SN - 2072-4292 VL - 14 IS - 18 ER - TY - JOUR A1 - Ha, Tuyen V. A1 - Huth, Juliane A1 - Bachofer, Felix A1 - Kuenzer, Claudia T1 - A review of Earth observation-based drought studies in Southeast Asia JF - Remote Sensing N2 - Drought is a recurring natural climatic hazard event over terrestrial land; it poses devastating threats to human health, the economy, and the environment. Given the increasing climate crisis, it is likely that extreme drought phenomena will become more frequent, and their impacts will probably be more devastating. Drought observations from space, therefore, play a key role in dissimilating timely and accurate information to support early warning drought management and mitigation planning, particularly in sparse in-situ data regions. In this paper, we reviewed drought-related studies based on Earth observation (EO) products in Southeast Asia between 2000 and 2021. The results of this review indicated that drought publications in the region are on the increase, with a majority (70%) of the studies being undertaken in Vietnam, Thailand, Malaysia and Indonesia. These countries also accounted for nearly 97% of the economic losses due to drought extremes. Vegetation indices from multispectral optical remote sensing sensors remained a primary source of data for drought monitoring in the region. Many studies (~21%) did not provide accuracy assessment on drought mapping products, while precipitation was the main data source for validation. We observed a positive association between spatial extent and spatial resolution, suggesting that nearly 81% of the articles focused on the local and national scales. Although there was an increase in drought research interest in the region, challenges remain regarding large-area and long time-series drought measurements, the combined drought approach, machine learning-based drought prediction, and the integration of multi-sensor remote sensing products (e.g., Landsat and Sentinel-2). Satellite EO data could be a substantial part of the future efforts that are necessary for mitigating drought-related challenges, ensuring food security, establishing a more sustainable economy, and the preservation of the natural environment in the region. KW - drought KW - drought impact KW - agricultural drought KW - hydrological drought KW - meteorological drought KW - earth observation KW - remote sensing KW - Southeast Asia KW - Mekong Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286258 SN - 2072-4292 VL - 14 IS - 15 ER - TY - JOUR A1 - Topsakal, Vedat A1 - Agrawal, Sumit A1 - Atlas, Marcus A1 - Baumgartner, Wolf-Dieter A1 - Brown, Kevin A1 - Bruce, Iain A. A1 - Dazert, Stefan A1 - Hagen, Rudolf A1 - Lassaletta, Luis A1 - Mlynski, Robert A1 - Raine, Christopher H. A1 - Rajan, Gunesh P. A1 - Schmutzhard, Joachim A1 - Sprinzl, Georg Mathias A1 - Staecker, Hinrich A1 - Usami, Shin-ichi A1 - Van Rompaey, Vincent A1 - Zernotti, Mario A1 - Heyning, Paul van de T1 - Minimally traumatic cochlear implant surgery: expert opinion in 2010 and 2020 JF - Journal of Personalized Medicine N2 - This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement. KW - electric acoustic stimulation (EAS) KW - cochlear implants KW - atraumatic surgery KW - hearing preservation KW - partial deafness treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288196 SN - 2075-4426 VL - 12 IS - 10 ER - TY - JOUR A1 - Dhaliwal, Anand A1 - Zamora, Tomas A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - Six commonly used postoperative radiographic alignment parameters do not predict clinical outcome scores after unrestricted caliper-verified kinematically aligned TKA JF - Journal of Personalized Medicine N2 - Background: Unrestricted caliper-verified kinematically aligned (KA) TKA restores patient’s prearthritic coronal and sagittal alignments, which have a wide range containing outliers that concern the surgeon practicing mechanical alignment (MA). Therefore, knowing which radiographic parameters are associated with dissatisfaction could help a surgeon decide whether to rely on them as criteria for revising an unhappy patient with a primary KA TKA using MA principles. Hence, we determined whether the femoral mechanical angle (FMA), hip–knee–ankle angle (HKAA), tibial mechanical angle (TMA), tibial slope angle (TSA), and the indicators of patellofemoral tracking, including patella tilt angle (PTA) and the lateral undercoverage of the trochlear resection (LUCTR), are associated with clinical outcome scores. Methods: Forty-three patients with a CT scan and skyline radiograph after a KA TKA with PCL retention and medial stabilized design were analyzed. Linear regression determined the strength of the association between the FMA, HKA angle, PTS, PTA, and LUCTR and the forgotten joint score (FJS), Oxford knee score (OKS), and KOOS Jr score obtained at a mean of 23 months. Results: There was no correlation between the FMA (range 2° varus to −10° valgus), HKAA (range 10° varus to −9° valgus), TMA (range 10° varus to −0° valgus), TSA (range 14° posterior to −4° anterior), PTA (range, −10° medial to 14° lateral), and the LUCTR resection (range 2 to 9 mm) and the FJS (median 83), the OKS (median 44), and the KOOS Jr (median 85) (r = 0.000 to 0.079). Conclusions: Surgeons should be cautious about using postoperative FMA, HKAA, TMA, TSA, PTA, and LUCTR values within the present study’s reported ranges to explain success and dissatisfaction after KA TKA. KW - total knee arthroplasty KW - kinematic alignment KW - reoperation KW - revision KW - phenotype Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288186 SN - 2075-4426 VL - 12 IS - 9 ER - TY - JOUR A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - Measurement of tibial orientation helps select the optimal insert thickness to personalize PCL tension in a medial ball-in-socket TKA JF - Journal of Personalized Medicine N2 - As the conformity of a medial ball-in-socket total knee arthroplasty (TKA) provides intrinsic anterior-posterior (A-P) stability, surgeons cannot rely on the manual examination of sagittal laxity to identify the optimal insert thickness. Instead, the present study determined whether measuring tibial axial orientation in extension and 90° flexion with an insert goniometer could identify the optimal thickness that, when implanted, provides high postoperative function. In twenty-two patients that underwent unrestricted caliper-verified kinematic alignment (KA) with a PCL retaining implant, two surgeons measured tibial orientation in extension and 90° flexion with 10, 11, 12, and 13 mm thick insert goniometers. Each TKA had one insert thickness that restored either the maximum external tibial orientation in extension, the maximum internal tibial orientation at 90° flexion, or both relative to 1 mm thinner and thicker inserts. In addition, the 6-month median [interquartile range] Forgotten Joint Score of 73 (54–87) and Oxford Knee Score of 42 (38–45) indicated high satisfaction and function. In conclusion, surgeons using a medial ball-in-socket TKA design can measure external tibial orientation in extension and internal tibial orientation at 90° flexion with an insert goniometer. Furthermore, implanting an insert with the thickness that provided the maximum orientation values resulted in high postoperative function, thereby personalizing PCL tension. KW - posterior cruciate ligament KW - tibial rotation KW - medial pivot KW - total knee arthroplasty KW - kinematic alignment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286232 SN - 2075-4426 VL - 12 IS - 9 ER - TY - JOUR A1 - Kirsten, Natalia A1 - Ohm, Frenz A1 - Gehrdau, Kathrin A1 - Girbig, Gefion A1 - Stephan, Brigitte A1 - Ben-Anaya, Nesrine A1 - Pinter, Andreas A1 - Bechara, Falk G. A1 - Presser, Dagmar A1 - Zouboulis, Christos C. A1 - Augustin, Matthias T1 - Switching from adalimumab originator to biosimilar in patients with hidradenitis suppurativa results in losses of response — data from the German HS registry HSBest JF - Life N2 - Since 2021, adalimumab biosimilar ABP 501 can be used alternatively to adalimumab originator (ADAO) in the treatment of hidradenitis suppurativa (HS). Effectiveness and safety data remain scarce. We investigated the impact of switching from ADAO to ABP 501 on disease severity and the occurrence of adverse events (AEs) in patients with HS. We analyzed clinical data on patients enrolled in the German HSBest registry. Evaluation outcomes were assessed at three time points (baseline of originator (t0), prior to switching to biosimilar (t1) and 12 to 14 weeks after switching (t2)) and included patient-reported AEs and disease severity using the International Hidradenitis Suppurativa Severity Score System (IHS4) score. In total, 94 patients were switched from ADAO to ABP 501. Overall, 33.3% (n = 31/94) of the patients developed AEs and/or loss of response (LoR) within 12 to 14 weeks after switching. Of these, 61.3% (n = 19/31) experienced LoR but no AEs, 22.6% (n = 7/31) LoR combined with AEs and 16.1% (n = 5/31) AEs only. Our study showed that switching HS patients from ADAO to ABP 501 does significantly affect treatment effectiveness. Switching patients who are on remission maintenance therapy should be viewed critically. KW - hidradenitis suppurativa KW - biologics KW - TNF alpha KW - adverse drug reaction KW - biosimilar KW - drug effectiveness KW - switching KW - adalimumab KW - registry Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288213 SN - 2075-1729 VL - 12 IS - 10 ER - TY - JOUR A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - A TKA insert with a lateral flat articular surface maximizes external and internal tibial orientations without anterior lift-off relative to low- and ultracongruent surfaces JF - Journal of Personalized Medicine N2 - Background: In total knee arthroplasty (TKA), inserts can have different levels of medial and lateral congruency determined by the acuteness of the upslopes of the anterior and posterior articular surfaces. The present study evaluated an insert with different levels of lateral congruency and a medial ball-in-socket congruency to test the hypothesis that a lateral flat (F) insert maximizes external tibial orientation at extension and internal orientation at 90° flexion and lowers the incidence of anterior lift-off relative to low-congruent (LC) and ultracongruent (UC) lateral inserts. Methods: Two surgeons treated 23 patients with unrestricted caliper-verified kinematic alignment (KA) and posterior cruciate ligament (PCL) retention. They randomly trialed inserts with a medial radial dial that functioned as a built-in goniometer by measuring the tibial orientation relative to a sagittal line on the femoral trial component. Anterior lift-off of the insert from the baseplate indicated PCL tightness. Results: The F insert’s mean of 9° of external tibial orientation was higher than that of the LC (5°, p < 0.0001) and UC inserts (2°, p < 0.0001). The −13° of internal tibial orientation at 90° flexion was higher than that of the LC (−9°, p < 0.0001) and UC inserts (−7°, p < 0.0001). The 0% incidence of anterior lift-off was less than that of the LC (26%) and UC inserts (57%) (p < 0.0001). Conclusions: Surgeons and implant manufacturers should know that adding congruency to the lateral articular surface limits external tibial orientation in extension and internal tibial orientation at 90° flexion and overtightens the PCL. These rotational limitations and flexion space tightness can adversely affect patellofemoral tracking and knee flexion. KW - total knee arthroplasty KW - kinematic alignment KW - implant design KW - PCL retention KW - congruency Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286142 SN - 2075-4426 VL - 12 IS - 8 ER - TY - JOUR A1 - Nanda, Indrajit A1 - Schröder, Sarah K. A1 - Steinlein, Claus A1 - Haaf, Thomas A1 - Buhl, Eva M. A1 - Grimm, Domink G. A1 - Weiskirchen, Ralf T1 - Rat hepatic stellate cell line CFSC-2G: genetic markers and short tandem repeat profile useful for cell line authentication JF - Cells N2 - Hepatic stellate cells (HSCs) are also known as lipocytes, fat-storing cells, perisinusoidal cells, or Ito cells. These liver-specific mesenchymal cells represent about 5% to 8% of all liver cells, playing a key role in maintaining the microenvironment of the hepatic sinusoid. Upon chronic liver injury or in primary culture, these cells become activated and transdifferentiate into a contractile phenotype, i.e., the myofibroblast, capable of producing and secreting large quantities of extracellular matrix compounds. Based on their central role in the initiation and progression of chronic liver diseases, cultured HSCs are valuable in vitro tools to study molecular and cellular aspects of liver diseases. However, the isolation of these cells requires special equipment, trained personnel, and in some cases needs approval from respective authorities. To overcome these limitations, several immortalized HSC lines were established. One of these cell lines is CFSC, which was originally established from cirrhotic rat livers induced by carbon tetrachloride. First introduced in 1991, this cell line and derivatives thereof (i.e., CFSC-2G, CFSC-3H, CFSC-5H, and CFSC-8B) are now used in many laboratories as an established in vitro HSC model. We here describe molecular features that are suitable for cell authentication. Importantly, chromosome banding and multicolor spectral karyotyping (SKY) analysis demonstrate that the CFSC-2G genome has accumulated extensive chromosome rearrangements and most chromosomes exist in multiple copies producing a pseudo-triploid karyotype. Furthermore, our study documents a defined short tandem repeat (STR) profile including 31 species-specific markers, and a list of genes expressed in CFSC-2G established by bulk mRNA next-generation sequencing (NGS). KW - liver KW - extracellular matrix KW - hepatic stellate cell KW - myofibroblast KW - fibrosis KW - stress fibers KW - spectral karyotyping KW - rhodamine–phalloidin stain KW - next-generation sequencing KW - STR profile Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288067 SN - 2073-4409 VL - 11 IS - 18 ER - TY - JOUR A1 - Kline, Rachel A. A1 - Lößlein, Lena A1 - Kurian, Dominic A1 - Aguilar Martí, Judit A1 - Eaton, Samantha L. A1 - Court, Felipe A. A1 - Gillingwater, Thomas H. A1 - Wishart, Thomas M. T1 - An optimized comparative proteomic approach as a tool in neurodegenerative disease research JF - Cells N2 - Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability. KW - proteomics KW - systems biology KW - experimental design KW - neurodegeneration KW - pathway analysis KW - data filtering Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285912 SN - 2073-4409 VL - 11 IS - 17 ER - TY - JOUR A1 - Wang, Chenglong A1 - Stöckl, Sabine A1 - Li, Shushan A1 - Herrmann, Marietta A1 - Lukas, Christoph A1 - Reinders, Yvonne A1 - Sickmann, Albert A1 - Grässel, Susanne T1 - Effects of extracellular vesicles from osteogenic differentiated human BMSCs on osteogenic and adipogenic differentiation capacity of naïve human BMSCs JF - Cells N2 - Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland. KW - extracellular vesicles KW - mesenchymal stem cells KW - osteogenic potential KW - osteogenic differentiation KW - adipogenic differentiation KW - ECM remodeling KW - bone regeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286112 SN - 2073-4409 VL - 11 IS - 16 ER - TY - JOUR A1 - Stratos, Ioannis A1 - Behrendt, Ann-Kathrin A1 - Anselm, Christian A1 - Gonzalez, Aldebarani A1 - Mittlmeier, Thomas A1 - Vollmar, Brigitte T1 - Inhibition of TNF-α restores muscle force, inhibits inflammation, and reduces apoptosis of traumatized skeletal muscles JF - Cells N2 - Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury. KW - muscle injury KW - regeneration KW - infliximab KW - tumor necrosis factor alpha Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286094 SN - 2073-4409 VL - 11 IS - 15 ER - TY - JOUR A1 - Liu, Sheng A1 - Bonalume, Veronica A1 - Gao, Qi A1 - Chen, Jeremy Tsung-Chieh A1 - Rohr, Karl A1 - Hu, Jing A1 - Carr, Richard T1 - Pre-synaptic GABA\(_A\) in NaV1.8\(^+\) primary afferents is required for the development of punctate but not dynamic mechanical allodynia following CFA inflammation JF - Cells N2 - Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA\(_A\) in NaV1.8-positive sensory neurons (Scn10a\(^{Cre}\);Gabrb3\(^{fl/fl}\)) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA\(_A\). Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA\(_A\) and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8\(^+\) afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA\(_A\) in NaV1.8\(^+\) nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits. KW - GABA\(_A\) KW - presynaptic inhibition KW - NaV1.8 KW - spinal dorsal horn KW - punctate mechanical allodynia KW - c-fos KW - electrical excitability KW - activity-dependent slowing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286081 SN - 2073-4409 VL - 11 IS - 15 ER - TY - JOUR A1 - Eder, Sascha A1 - Hollmann, Claudia A1 - Mandasari, Putri A1 - Wittmann, Pia A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Fink, Julian A1 - Seibel, Jürgen A1 - Schneider-Schaulies, Jürgen A1 - Stigloher, Christian A1 - Beyersdorf, Niklas A1 - Dembski, Sofia T1 - Synthesis and characterization of ceramide-containing liposomes as membrane models for different T cell subpopulations JF - Journal of Functional Biomaterials N2 - A fine balance of regulatory (T\(_{reg}\)) and conventional CD4\(^+\) T cells (T\(_{conv}\)) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the T\(_{reg}\)/T\(_{conv}\) balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse T\(_{reg}\) and T\(_{conv}\) with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C\(_{16}\)-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into T\(_{reg}\) and T\(_{conv}\) reflect differences in the ceramide content of cellular membranes. KW - liposome KW - ceramide KW - cell membrane model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286130 SN - 2079-4983 VL - 13 IS - 3 ER - TY - JOUR A1 - Solimando, Antonio Giovanni A1 - Krebs, Markus A1 - Bittrich, Max A1 - Einsele, Hermann T1 - The urgent need for precision medicine in cancer and its microenvironment: the paradigmatic case of multiple myeloma JF - Journal of Clinical Medicine N2 - No abstract available KW - precision medicine KW - multiple myeloma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288164 SN - 2077-0383 VL - 11 IS - 18 ER - TY - JOUR A1 - Helmer, Philipp A1 - Helf, Daniel A1 - Sammeth, Michael A1 - Winkler, Bernd A1 - Hottenrott, Sebastian A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - The use of non-invasive continuous blood pressure measuring (ClearSight\(^®\)) during central neuraxial anaesthesia for caesarean section — a retrospective validation study JF - Journal of Clinical Medicine N2 - Background: The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring. Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight\(^®\) (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight\(^®\) through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight\(^®\) to oscillometric blood pressure measurement in regard of comfort and handling. KW - volume clamp KW - epidural anaesthesia KW - supine hypotensive syndrome KW - ClearSight\(^®\) KW - Bland–Altman KW - Fisher Z-score transformation KW - Pearson correlation coefficient Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286042 SN - 2077-0383 VL - 11 IS - 15 ER - TY - JOUR A1 - Ben Khaled, Najib A1 - Hammer, Katharina A1 - Ye, Liangtao A1 - Alnatsha, Ahmed A1 - Widholz, Sebastian A. A1 - Piseddu, Ignazio A1 - Sirtl, Simon A1 - Schneider, Julia A1 - Munker, Stefan A1 - Mahajan, Ujjwal Mukund A1 - Montero, Juan José A1 - Griger, Joscha A1 - Mayerle, Julia A1 - Reiter, Florian P. A1 - De Toni, Enrico N. T1 - TRAIL receptor targeting agents potentiate PARP inhibitor efficacy in pancreatic cancer independently of BRCA2 mutation status JF - Cancers N2 - Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists. KW - apoptosis KW - DNA damage KW - pancreatic neoplasms KW - poly(ADP-ribose) polymerase inhibitors KW - TNF-related apoptosis-inducing ligand Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290884 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Grünwald, Viktor A1 - Pink, Daniel A1 - Egerer, Gerlinde A1 - Schalk, Enrico A1 - Augustin, Marinela A1 - Deinzer, Christoph K. W. A1 - Kob, Viola A1 - Reichert, Dietmar A1 - Kebenko, Maxim A1 - Brandl, Stephan A1 - Hahn, Dennis A1 - Lindner, Lars H. A1 - Hoiczyk, Mathias A1 - Ringsdorf, Uta A1 - Hanker, Lars C. A1 - Hempel, Dirk A1 - De Rivas, Beatriz A1 - Wismann, Tobias A1 - Ivanyi, Philipp T1 - Trabectedin for patients with advanced soft tissue sarcoma: a non-interventional, prospective, multicenter, phase IV trial JF - Cancers N2 - This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile. KW - trabectedin KW - STS KW - sarcoma KW - non-interventional KW - prospective Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290898 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Woźnicki, Piotr A1 - Laqua, Fabian Christopher A1 - Messmer, Katharina A1 - Kunz, Wolfgang Gerhard A1 - Stief, Christian A1 - Nörenberg, Dominik A1 - Schreier, Andrea A1 - Wójcik, Jan A1 - Ruebenthaler, Johannes A1 - Ingrisch, Michael A1 - Ricke, Jens A1 - Buchner, Alexander A1 - Schulz, Gerald Bastian A1 - Gresser, Eva T1 - Radiomics for the prediction of overall survival in patients with bladder cancer prior to radical cystectomy JF - Cancers N2 - (1) Background: To evaluate radiomics features as well as a combined model with clinical parameters for predicting overall survival in patients with bladder cancer (BCa). (2) Methods: This retrospective study included 301 BCa patients who received radical cystectomy (RC) and pelvic lymphadenectomy. Radiomics features were extracted from the regions of the primary tumor and pelvic lymph nodes as well as the peritumoral regions in preoperative CT scans. Cross-validation was performed in the training cohort, and a Cox regression model with an elastic net penalty was trained using radiomics features and clinical parameters. The models were evaluated with the time-dependent area under the ROC curve (AUC), Brier score and calibration curves. (3) Results: The median follow-up time was 56 months (95% CI: 48–74 months). In the follow-up period from 1 to 7 years after RC, radiomics models achieved comparable predictive performance to validated clinical parameters with an integrated AUC of 0.771 (95% CI: 0.657–0.869) compared to an integrated AUC of 0.761 (95% CI: 0.617–0.874) for the prediction of overall survival (p = 0.98). A combined clinical and radiomics model stratified patients into high-risk and low-risk groups with significantly different overall survival (p < 0.001). (4) Conclusions: Radiomics features based on preoperative CT scans have prognostic value in predicting overall survival before RC. Therefore, radiomics may guide early clinical decision-making. KW - bladder cancer KW - radical cystectomy KW - radiomics KW - outcome prediction Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288098 SN - 2072-6694 VL - 14 IS - 18 ER - TY - JOUR A1 - Diefenhardt, Markus A1 - Martin, Daniel A1 - Ludmir, Ethan B. A1 - Fleischmann, Maximilian A1 - Hofheinz, Ralf-Dieter A1 - Ghadimi, Michael A1 - Kosmala, Rebekka A1 - Polat, Bülent A1 - Friede, Tim A1 - Minsky, Bruce D. A1 - Rödel, Claus A1 - Fokas, Emmanouil T1 - Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial JF - Cancers N2 - Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making. KW - rectal cancer KW - toxicity KW - neoadjuvant KW - chemoradiotherapy KW - risk score Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288081 SN - 2072-6694 VL - 14 IS - 18 ER -