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Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer
(2020)
Background: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC.
Methods: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0–100), which were summarized to the overall VAS score.
Results: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (− 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (− 7.82 vs. non-responders − 1.97, p = 0.0005). The VAS for pain (− 16.37 vs. non-responders − 8.89, p = 0.001) and swallowing of solid food (− 16.67 vs. non-responders − 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05–1.20, p = 0.0009).
Conclusion: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC.
Trial registration: ClinicalTrials.gov, NCT00122460. Registered 22 Juli 2005,
Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii (rg ≡ GM/c2) scales in nearby sources. Centaurus A is the closest radio-loud source to Earth. It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations, we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 rg scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses.
Oligonucleotides suppress PKB/Akt and act as superinductors of apoptosis in human keratinocytes
(2009)
DNA oligonucleotides (ODN) applied to an organism are known to modulate the innate and adaptive immune system. Previous studies showed that a CpG-containing ODN (CpG-1-PTO) and interestingly, also a non-CpG-containing ODN (nCpG- 5-PTO) suppress inflammatory markers in skin. In the present study it was investigated whether these molecules also influence cell apoptosis. Here we show that CpG-1-PTO, nCpG-5-PTO, and also natural DNA suppress the phosphorylation of PKB/Akt in a cell-type-specific manner. Interestingly, only epithelial cells of the skin (normal human keratinocytes, HaCaT and A-431) show a suppression of PKB/Akt. This suppressive effect depends from ODN lengths, sequence and backbone. Moreover, it was found that TGFa-induced levels of PKB/Akt and EGFR were suppressed by the ODN tested. We hypothesize that this suppression might facilitate programmed cell death. By testing this hypothesis we found an increase of apoptosis markers (caspase 3/7, 8, 9, cytosolic cytochrome c, histone associated DNA fragments, apoptotic bodies) when cells were treated with ODN in combination with low doses of staurosporin, a wellknown pro-apoptotic stimulus. In summary the present data demonstrate DNA as a modulator of apoptosis which specifically targets skin epithelial cells.
Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27–0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33–0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.
Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
(2022)
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell–mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell–mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Land surface and hydrologic models (LSMs/HMs) are used at diverse spatial resolutions ranging from catchment-scale (1–10 km) to global-scale (over 50 km) applications. Applying the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the chosen resolution, i.e., fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent hydrologic parameter fields. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB, and WaterGAP models demonstrate the pitfalls of deficient parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge's 1982 statement on the unsolved problem of parameterization in these models remains true. Based on a review of existing parameter regionalization techniques, we postulate that the multiscale parameter regionalization (MPR) technique offers a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. Herein, we develop a general model protocol to describe how MPR can be applied to a particular model and present an example application using the PCR-GLOBWB model. Finally, we discuss potential advantages and limitations of MPR in obtaining the seamless prediction of hydrological fluxes and states across spatial scales.
Land surface and hydrologic models (LSM/HM) are used at diverse spatial resolutions ranging from 1-10 km in catchment-scale applications to over 50 km in global-scale applications. Application of the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the model resolution and fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent and realistic parameter fields for land surface geophysical properties. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB and WaterGAP models are conducted to demonstrate the pitfalls of poor parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge’s 1982 statement on the unsolved problem of parameterization in these models remains true. We provide a short review of existing parameter regionalization techniques and discuss a method for obtaining seamless hydrological predictions of water fluxes and states across multiple spatial resolutions. The multiscale parameter regionalization (MPR) technique is a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. A general model protocol is presented to describe how MPR can be applied to a specific model, with an example of this application using the PCR-GLOBWB model. Applying MPR to PCR-GLOBWB substantially improves the flux-matching condition. Estimation of evapotranspiration without MPR at 5 arcmin and 30 arcmin spatial resolutions for the Rhine river basin results in a difference of approximately 29%. Applying MPR reduce this difference to 9%. For total soil water, the differences without and with MPR are 25% and 7%, respectively.
Background Since June 2002, revised regulations in Germany have required "Emergency Medical Care" as an interdisciplinary subject, and state that emergency treatment should be of increasing importance within the curriculum. A survey of the current status of undergraduate medical education in emergency medical care establishes the basis for further committee work. Methods Using a standardized questionnaire, all medical faculties in Germany were asked to answer questions concerning the structure of their curriculum, representation of disciplines, instructors' qualifications, teaching and assessment methods, as well as evaluation procedures. Results Data from 35 of the 38 medical schools in Germany were analysed. In 32 of 35 medical faculties, the local Department of Anaesthesiology is responsible for the teaching of emergency medical care; in two faculties, emergency medicine is taught mainly by the Department of Surgery and in another by Internal Medicine. Lectures, seminars and practical training units are scheduled in varying composition at 97% of the locations. Simulation technology is integrated at 60% (n=21); problem-based learning at 29% (n=10), e-learning at 3% (n=1), and internship in ambulance service is mandatory at 11% (n=4). In terms of assessment methods, multiple-choice exams (15 to 70 questions) are favoured (89%, n=31), partially supplemented by open questions (31%, n=11). Some faculties also perform single practical tests (43%, n=15), objective structured clinical examination (OSCE; 29%, n=10) or oral examinations (17%, n=6). Conclusion Emergency Medical Care in undergraduate medical education in Germany has a practical orientation, but is very inconsistently structured. The innovative options of simulation technology or state-of-the-art assessment methods are not consistently utilized. Therefore, an exchange of experiences and concepts between faculties and disciplines should be promoted to guarantee a standard level of education in emergency medical care.
Chronic inflammation is characterized by persisting leukocyte infiltration of the affected tissue, which is enabled by activated endothelial cells (ECs). Chronic inflammatory diseases remain a major pharmacotherapeutic challenge, and thus the search for novel drugs and drug targets is an ongoing demand. We have identified the natural product vioprolide A (vioA) to exert anti-inflammatory actions in vivo and in ECs in vitro through inhibition of its cellular target nucleolar protein 14 (NOP14). VioA attenuated the infiltration of microglia and macrophages during laser-induced murine choroidal neovascularization and the leukocyte trafficking through the vascular endothelium in the murine cremaster muscle. Mechanistic studies revealed that vioA downregulates EC adhesion molecules and the tumor necrosis factor receptor (TNFR) 1 by decreasing the de novo protein synthesis in ECs. Most importantly, we found that inhibition of importin-dependent NF-ĸB p65 nuclear translocation is a crucial part of the action of vioA leading to reduced NF-ĸB promotor activity and inflammatory gene expression. Knockdown experiments revealed a causal link between the cellular target NOP14 and the anti-inflammatory action of vioA, classifying the natural product as unique drug lead for anti-inflammatory therapeutics.
High-throughput protein localization studies require multiple strategies. Mass spectrometric analysis of defined cellular fractions is one of the complementary approaches to a diverse array of cell biological methods. In recent years, the protein content of different cellular (sub-)compartments was approached. Despite of all the efforts made, the analysis of membrane fractions remains difficult, in that the dissection of the proteomes of the envelope membranes of chloroplasts or mitochondria is often not reliable because sample purity is not always warranted. Moreover, proteomic studies are often restricted to single (model) species, and therefore limited in respect to differential individual evolution. In this study we analyzed the chloroplast envelope proteomes of different plant species, namely, the individual proteomes of inner and outer envelope (OE) membrane of Pisum sativum and the mixed envelope proteomes of Arabidopsis thaliana and Medicago sativa. The analysis of all three species yielded 341 identified proteins in total, 247 of them being unique. 39 proteins were genuine envelope proteins found in at least two species. Based on this and previous envelope studies we defined the core envelope proteome of chloroplasts. Comparing the general overlap of the available six independent studies (including ours) revealed only a number of 27 envelope proteins. Depending on the stringency of applied selection criteria we found 231 envelope proteins, while less stringent criteria increases this number to 649 putative envelope proteins. Based on the latter we provide a map of the outer and inner envelope core proteome, which includes many yet uncharacterized proteins predicted to be involved in transport, signaling, and response. Furthermore, a foundation for the functional characterization of yet unidentified functions of the inner and OE for further analyses is provided.
Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.
Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.
Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.
Trial registration: ClinicalTrials.gov (identifier: NCT03369210).
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Biodiversity is a cornerstone of human health and well-being. However, while evidence of the contributions of nature to human health is rapidly building, research into how biodiversity relates to human health remains limited in important respects. In particular, a better mechanistic understanding of the range of pathways through which biodiversity can influence human health is needed. These pathways relate to both psychological and social processes as well as biophysical processes. Building on evidence from across the natural, social and health sciences, we present a conceptual framework organizing the pathways linking biodiversity to human health. Four domains of pathways—both beneficial as well as harmful—link biodiversity with human health: (i) reducing harm (e.g. provision of medicines, decreasing exposure to air and noise pollution); (ii) restoring capacities (e.g. attention restoration, stress reduction); (iii) building capacities (e.g. promoting physical activity, transcendent experiences); and (iv) causing harm (e.g. dangerous wildlife, zoonotic diseases, allergens). We discuss how to test components of the biodiversity-health framework with available analytical approaches and existing datasets. In a world with accelerating declines in biodiversity, profound land-use change, and an increase in non-communicable and zoonotic diseases globally, greater understanding of these pathways can reinforce biodiversity conservation as a strategy for the promotion of health for both people and nature. We conclude by identifying research avenues and recommendations for policy and practice to foster biodiversity-focused public health actions.
Background: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents.
Methods: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods.
Discussion: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life.
Trial registration: ClinicalTrials.gov: NCT04101123.
This summary provides an overview of how new therapies or new aspects of established therapies relate to the latest findings. Neoadjuvant therapy, local therapy, new aspects of systemic therapy, and prognostic and predictive factors are presented. In the neoadjuvant setting, the association between pathological complete response (pCR) and prognosis is still of interest as is the identification of new molecular predictors for new therapies such as CDK4/6 inhibitors. As regards surgical treatment, the target is still to reduce the aggressiveness of surgery. To achieve this, a better understanding particularly of ductal carcinoma in situ is required. With regard to systemic therapy, more data on the best combinations and therapy sequences for existing therapies is available. Finally, the use of prognostic and predictive factors may help to avoid overtreatment and ensure that patients only receive therapies which have been shown to be effective for their specific condition and have fewer side effects.