Refine
Has Fulltext
- yes (21)
Is part of the Bibliography
- yes (21)
Year of publication
Document Type
- Journal article (21)
Keywords
- ARIA (2)
- Anorganische Chemie (2)
- AIRWAYS ICPs (1)
- ANTARES telescope (1)
- Biochemie (1)
- Biotransformation (1)
- CARAT (1)
- CaMKII (1)
- Chronic respiratory diseases (1)
- DNA damage (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (6)
- Institut für Klinische Epidemiologie und Biometrie (3)
- Institut für Theoretische Physik und Astrophysik (3)
- Kinderklinik und Poliklinik (3)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (3)
- Institut für Anorganische Chemie (2)
- Institut für Virologie und Immunbiologie (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Frauenklinik und Poliklinik (1)
- Institut für Anatomie und Zellbiologie (1)
- Institut für Molekulare Infektionsbiologie (1)
- Institut für Pharmakologie und Toxikologie (1)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (1)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (1)
- Medizinische Klinik und Poliklinik I (1)
- Medizinische Klinik und Poliklinik II (1)
- Poliklinik für Zahnerhaltung und Parodontologie (1)
EU-Project number / Contract (GA) number
- 965286 (1)
Background
The impact of hospital volume after rectal cancer surgery is seldom investigated. This study aimed to analyse the impact of annual rectal cancer surgery cases per hospital on postoperative mortality and failure to rescue.
Methods
All patients diagnosed with rectal cancer and who had a rectal resection procedure code from 2012 to 2015 were identified from nationwide administrative hospital data. Hospitals were grouped into five quintiles according to caseload. The absolute number of patients, postoperative deaths and failure to rescue (defined as in‐hospital mortality after a documented postoperative complication) for severe postoperative complications were determined.
Results
Some 64 349 patients were identified. The overall in‐house mortality rate was 3·9 per cent. The crude in‐hospital mortality rate ranged from 5·3 per cent in very low‐volume hospitals to 2·6 per cent in very high‐volume centres, with a distinct trend between volume categories (P < 0·001). In multivariable logistic regression analysis using hospital volume as random effect, very high‐volume hospitals (53 interventions/year) had a risk‐adjusted odds ratio of 0·58 (95 per cent c.i. 0·47 to 0·73), compared with the baseline in‐house mortality rate in very low‐volume hospitals (6 interventions per year) (P < 0·001). The overall postoperative complication rate was comparable between different volume quintiles, but failure to rescue decreased significantly with increasing caseload (15·6 per cent after pulmonary embolism in the highest volume quintile versus 38 per cent in the lowest quintile; P = 0·010).
Conclusion
Patients who had rectal cancer surgery in high‐volume hospitals showed better outcomes and reduced failure to rescue rates for severe complications than those treated in low‐volume hospitals.
SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.
Background:
Colonic cancer is the most common cancer of the gastrointestinal tract. The aim of this study was to determine mortality rates following colonic cancer resection and the effect of hospital caseload on in-hospital mortality in Germany.
Methods:
Patients admitted with a diagnosis of colonic cancer undergoing colonic resection from 2012 to 2015 were identifed from a nationwide registry using procedure codes. The outcome measure was in-hospital mortality. Hospitals were ranked according to their caseload for colonic cancer resection, and patients were categorized into five subgroups on the basis of hospital volume.
Results:
Some 129 196 colonic cancer resections were reviewed. The overall in-house mortality rate was 5⋅8 per cent, ranging from 6⋅9 per cent (1775 of 25 657 patients) in very low-volume hospitals to 4⋅8 per cent (1239 of 25 825) in very high-volume centres (P < 0⋅001). In multivariable logistic regression analysis the risk-adjusted odds ratio for in-house mortality was 0⋅75 (95 per cent c.i. 0⋅66 to 0⋅84) in very high-volume hospitals performing a mean of 85⋅0 interventions per year, compared with that in very low-volume hospitals performing a mean of only 12⋅7 interventions annually, after adjustment for sex, age, co-morbidity, emergency procedures, prolonged mechanical ventilation and transfusion.
Conclusion:
In Germany, patients undergoing colonic cancer resections in high-volume hospitals had with improved outcomes compared with patients treated in low-volume hospitals
In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
(2015)
Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi-or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS\(^{61K}\) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.
Neutralizing monoclonal antibodies define two different functional sites in human interleukin-4
(1994)
Human interleukin-4 (IL-4) is a small four-helix-bundle protein which is essential for organizing defense reactions against macroparasites, in particular helminths. Human IL-4 also appears to exert a pathophysiological role during various IgE-mediated allergic diseases. Seven different monoclonal antibodies neutralizing the activity of human IL-4 were studied in order to identify functionally important epitopes. A collection of 41 purified IL-4 variants was used to analyse how defined amino acid replacements affect binding affinity for each individual mAb. Specific amino acid positions could be assigned to four different epitopes. mAbs recognizing epitopes on helix A and/or C interfered with IL-4 receptor binding and thus inhibited IL-4 function. However, other mAbs also inhibiting IL-4 function recognized an epitope on helix D of IL-4 and did not inhibit IL-4 binding to the receptor protein. One mAb, recognizing N-terminal and C-terminal residues, partially competed for binding to the receptor. The results of these mAb epitope analyses confirm and extend previous data on the functional consequences of the amino acid replacements which showed that amino acid residues in helices A and C of IL-4 provide a binding site for the cloned IL-4 receptor and that a signalling site in helix D interacts with a further receptor protein.
No abstract available.
There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation.
Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population.
Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR.
Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 %) and in rheumatoid factor negative polyarthritis (30.5 %) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 %) and in enthesitis-related arthritis (17 %). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 % 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 % 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 % 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant.
Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA.
Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca\(^{2+}\)-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I\(_{CaL}\) seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I\(_{NaL}\) and Ca\(^{2+}\)-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.