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- glioblastoma (3)
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González-González, Ana I. ; Schmucker, Christine ; Nothacker, Julia ; Nguyen, Truc Sophia ; Brückle, Maria-Sophie ; Blom, Jeanet ; Akker, J. M. van den ; Röttger, Kristian ; Wegwarth, Odette ; Hoffmann, Tammy ; Gerlach, Ferdinand M. ; Straus, Sharon E. ; Meerpohl, Jörg J. ; Muth, Christiane
Introduction End-of-life care is an essential task performed by most healthcare providers and often involves decision-making about how and where patients want to receive care. To provide decision support to healthcare professionals and patients in this difficult situation, we will systematically review a knowledge cluster of the end-of-life care preferences of older patients with multimorbidity that we previously identified using an evidence map.
Methods and analysis We will systematically search for studies reporting end-of-life care preferences of older patients (mean age ≥60) with multimorbidity (≥2 chronic conditions) in MEDLINE, CINAHL, PsycINFO, Social Sciences Citation Index, Social Sciences Citation Index Expanded, PSYNDEX and The Cochrane Library from inception to September 2019. We will include all primary studies that use quantitative, qualitative and mixed methodologies, irrespective of publication date and language.
Two independent reviewers will assess eligibility, extract data and describe evidence in terms of study/population characteristics, preference assessment method and end-of-life care elements that matter to patients (eg, life-sustaining treatments). Risk of bias/applicability of results will be independently assessed by two reviewers using the Mixed-Methods Appraisal Tool. Using a convergent integrated approach on qualitative/quantitative studies, we will synthesise information narratively and, wherever possible, quantitatively.
Ethics and dissemination Due to the nature of the proposed systematic review, ethics approval is not required. Results from our research will be disseminated at relevant (inter-)national conferences and via publication in peer-reviewed journals. Synthesising evidence on end-of-life care preferences of older patients with multimorbidity will improve shared decision-making and satisfaction in this final period of life.
BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells
(2021)
Linder, Benedikt ; Klein, Caterina ; Hoffmann, Marina E. ; Bonn, Florian ; Đikić, Ivan ; Kögel, Donat
By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.
BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells
(2021)
Linder, Benedikt ; Klein, Caterina ; Hoffmann, Marina E. ; Bonn, Florian ; Đikić, Ivan ; Kögel, Donat
By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.
Tilgner, Andreas ; Schöne, Luisa ; Bräuer, Peter ; Pinxteren, Dominik van ; Hoffmann, E. ; Spindler, Gerald ; Mertes, Stephan ; Birmili, Wolfram ; Otto, Robert ; Merkel, Maik ; Weinhold, Kay ; Wiedensohler, Alfred ; Deneke, Hartwig ; Haunold, Werner ; Engel, Andreas ; Wéber, A. ; Hartmut, Herrmann
This study presents a comprehensive and critical assessment of the meteorological conditions and atmospheric flow during the Lagrangian-type "Hill Cap Cloud Thuringia 2010" experiment (HCCT-2010). HCCT-2010 was performed in September and October 2010 at Mt. Schmücke in the Thuringian forest, Germany, applying three measurements sites (upwind, in-cloud, downwind) to study physical and chemical aerosol-cloud-interactions. A Lagrangian-type hill cap cloud experiment requires suitable cloud and particularly connected airflow conditions, i.e. representative air masses at the different measurement sites. Therefore, the present study aimed at the identification of time periods during the 6-weeks duration of the campaign, where such conditions were fulfilled and which can be used in further data examinations.
The following topics were studied in detail: (i) the general synoptic weather situations including the mesoscale flow conditions by means of a classification of advected air masses and calculation of non-dimensional flow parameters (e.g. Froude number), (ii) local meteorological conditions, including synoptic front passages, the presence of orographic or frontal cloudiness, cloud base heights and vertical stratification, and (iii) local flow conditions by means of statistical analyses using the quasi-inert trace gas ozone and selected size bins of particle number size distributions as well as SF6 tracer experiments in the campaign area. A comprehensive analyses using statistical measures such as the COD (Coefficient Of Divergence) and cross-correlation have been carried out for the first time in the context of a Lagrangian-type hill cap cloud experiment. Suitable criteria for the aimed statistical analyses were thus developed and applied in the present study to characterise the local flow connectivity in detail.
The comprehensive examination resulted in a total of 14 so-called "Full Cloud Events" (FCE), which are shown to conform to the Lagrange-type experimental philosophy of HCCT-2010. In addition, 15 so-called "Non-Cloud Events" (NCEs) could be established, which can be used as reference cases as they provide similarly suitable flow conditions but no cloud at the summit site. Orographic cloudiness was identified for approx. one third of the FCE periods, while about two thirds were associated to synoptic fronts. The statistical flow analyses indicate the existence of a strong link between the sites during the events, particularly under constant south-westerly flow conditions, high wind speeds and slightly stable stratification. The COD analyses using continuously measured concentrations of ozone and the 49 nm diameter particle bin revealed particularly for COD values below 0.1 very consistent time series, i.e. closely linked air masses between the different sites. The cross-correlation analysis revealed under connected flow conditions typical overflow times of about 15 to 30 min between the two valley sites. Additionally, the performed SF6 tracer experiments during the campaign clearly demonstrate that under appropriate meteorological conditions a Lagrangian-type approach is valid and that the connected flow validation procedure developed in this work is suitable for identifying such conditions. Finally, an overall evaluation of the identified FCEs is presented, which provides the basis for subsequent investigations of the measured chemical and physical data during HCCT-2010.
Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice
(2022)
Langer, Florian ; Gerlach, Horst E. ; Schimke, Alexandra ; Heinken, Andreas ; Hoffmann, Ulrich ; Noppeney, Thomas ; Pittrow, David ; Klotsche, Jens ; Rabe, Eberhard ; Bauersachs, Rupert
Highlights
• In acute isolated SVT, the prevalence of cancer is almost 7 %.
• Cancer increases the SVT-associated VTE risk at 3 and 12 months.
• Cancer patients with isolated SVT may benefit from prolonged anticoagulation.
Abstract
Background: Despite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice.
Methods: INSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed.
Results: Of 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant.
Conclusion: Cancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.
ClinicalTrials.gov identifier: NCT02699151.
Streit, Sven ; Verschoor, Marjolein ; Rodond, Nicolas ; Bonfim, Daiana ; Burman, Robert Anders ; Collins, Claire ; Gerasimovska Kitanovska, Biljana ; Gintere, Sandra ; Gómez Bravo, Raquel ; Hoffmann, Kathryn ; Iftode, Claudia ; Johansen, Kasper ; Kerse, Ngaire ; Koskela, Tuomas H. ; Kreitmayer Peštić, Sanda ; Kurpas, Donata ; Mallen, Christian David ; Maisoneuve, Hubert ; Merlo, Christoph ; Müller, Yolanda ; Muth, Christiane ; Šter, Marija Petek ; Petrazzuoli, Ferdinando ; Rosemann, Thomas ; Sattler, Martin ; Švadlenková, Zuzana ; Tatsioni, Athina ; Thulesius, Hans ; Tkachenko, Victoria ; Torzsa, Peter ; Tsopra, Rosy ; Canan, Tuz ; Viegas, Rita P. A. ; Vinker, Shlomo ; Margot W. M. de, Waal ; Zeller, Andreas ; Gussekloo, Jacobijn ; Poortvliet, Rosalinde K. E.
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Bauersachs, Rupert ; Gerlach, Horst E. ; Heinken, Andreas ; Hoffmann, Ulrich ; Langer, Florian ; Noppeney, Thomas ; Pittrow, David ; Klotsche, Jens ; Rabe, Eberhard
Objective: Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions.
Methods: Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding.
Results: A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m2). SVT was below the knee in 54.5%, above the knee in 26.7%, above and below the knee in 18.8%. At baseline, 93.6% received pharmacological treatment (65.7% fondaparinux, 23.2% heparins, 4.3% direct oral anticoagulants [DOACs], 14.5% analgesics), 77.0% compression treatment, and 1.9% surgery; 6.4% did not receive any anticoagulation. The primary outcome occurred in 5.8%; 4.7% had recurrent or extended SVT, 1.7% DVT, and 0.8% PE. Clinically relevant non-major bleeding occurred in 1.2% and major bleeding in 0.3%. Complete clinical recovery of SVT was reported in 708 patients (62.4%). Primary outcome adjusted by propensity score and for treatment duration was lower with fondaparinux compared with low molecular weight heparin (4.4% vs. 9.6%; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.3 - 0.9; p = .017). On multivariable analysis, associated factors for primary outcome included another SVT prior to the present SVT event (HR 2.3), age per year (HR 0.97), duration of drug treatment per week (HR 0.92), and thrombus length (HR 1.03).
Conclusion: At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.