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Optimized HF therapy in patients with advanced cancer in palliative care: dosing strategies from the EMPATICC trial
Get PDFCardiac wasting occurs in patients with endstage cancer, leading to the development of heart failure (HF)like symptoms characterized by dyspnea, reduced physical function, and diminished quality of life. EMPATICC (EMPower the heArt of patients with TermInal Cancer using Cardiac medicines) is a randomized controlled trial designed to evaluate the impact of optimized HF therapy in patients with advanced cancer receiving specialized palliative care. Given the susceptibility to adverse drug events in this vulnerable population, the trial employed a protocoldriven approach for the initiation and titration of each medication.EMPATICC is a multicenter, randomized, doubleblind, controlled, proofofconcept trial that enrolled 93 patients with stage IV solid tumors (per Union for International Cancer Control [UICC]), under palliative care, with clinical features indicating cardiovascular risk and functional limitation. Participants were randomized 1:1 to receive optimized HF therapy, including sacubitril/valsartan, empagliflozin, ivabradine, and ferric carboxymaltose (FCM), or 14 placebo therapies on top of usual care. All trial medications (or placebo) that was available in tablet form were provided in prepacked containers to support blinding. Blue placebo tablets were used for empagliflozin, white tablets for sacubitril/valsartan, and pink tablets for ivabradine. Blinded staff members did not have access to individual tablet packaging or knowledge of color allocations. Additionally, the meaning of the colorcoded tablets was not disclosed to the blind staff members throughout the trial. Dosing protocols were guided by predefined criteria, including blood pressure, renal function, heart rate, hemoglobin, and body weight, and they were implemented by unblinded staff. Algorithms accounted for prior RAAS inhibitor exposure when initiating sacubitril/valsartan; ensured hemodynamic stability and sinus rhythm for ivabradine; assessed renal reserve when starting empagliflozin to support safe and effective titration; and accounted for body weight and hemoglobin levels when initiating FCM. To ensure consistent implementation across five centers in Germany, visual flowcharts were designed.The EMPATICC trial provides a practical, protocoldriven approach for delivering HF therapy in the palliative oncology setting. Dosing algorithms outlined in this study could serve as a model for structured cardiovascular care in patients with advanced cancer
Long-read ONT-dRNA and PacBio Kinnex full-length RNA sequencing of UPF1 depletion in human colorectal adenocarcinoma cell line HCT116 via the auxin-inducible degron (AID) system
No full textUPF1 is a multi-domain RNA helicase that constantly monitors the transcriptome by non-specifically binding to mRNAs, dissociating from non-target transcripts, and initiating degradation on selected target RNAs via multiple proposed pathways such as nonsense-mediated decay (NMD). NMD is a translation-coupled mechanism that targets mRNAs harboring a premature stop codon (PTC) for degradation, thereby serving as a quality control and gene regulatory pathway ensuring transcriptome integrity. The UPF1 gene is essential in cultured human cells and previous studies relied mostly on RNA interference to downregulate UPF1. Here we established an auxin-inducible UPF1 degron system in the human colorectal adenocarcinoma cell line HCT116 by first inserting the auxin receptor F-box protein-encoding AtAFB2-mCherry in the AAVS1 locus, followed by tagging UPF1 at the N-terminus with an V5-AID-tag (AID = miniIAA7 = AtIAA7 amino acids 37–104). With this cell line and using long-read sequencing approaches (ONT-direct RNA sequencing [ONT-dRNA] and PacBio Kinnex full-length RNA sequencing) we wanted to explore the changes in transcript isoform composition upon rapid depletion of UPF1. To this end, depletion of UPF1 was induced with 500 µM indole-3-acetic acid (IAA) for 12h. As control untreated cells were used
An explorative analysis of plasma biomarkers associated with cerebral amyloid angiopathy
Get PDFBACKGROUND: Cerebral amyloid angiopathy (CAA) remains diagnostically challenging, particularly in asymptomatic individuals. While CAA often co-exists with Alzheimer's disease (AD), it may even have a direct impact on AD pathophysiology and the cognitive decline within the clinical course of AD. While fluid biomarkers are well-established for AD pathology, reliable markers to improve the characterization of CAA are lacking. METHODS: We analyzed two subsets of participants from the Alzheimer's Disease Neuroimaging Initiative: one with available T2*-weighted gradient echo magnetic resonance imaging (MRI) (n=21) and another with postmortem neuropathological data (n=24), all with available plasma biomarkers from a 145-analyte multiplex immunoassay panel. We defined CAA as two or more lobar microbleeds in MRI or moderate to severe neocortical amyloid angiopathy in neuropathological examination. Plasma analytes were assessed twice per subject, one year apart, with the earlier sample obtained up to 6.6 years prior to either the first MRI or neuropathological examination. Non-parametric correlation and receiver operating characteristic curves were mainly reported. RESULTS: In both cohorts, various markers related to inflammation, lipid metabolism, and cell adhesion were associated with CAA proxy measures. Specifically, both increased (Osteopontin, VCAM-1) and decreased (vitronectin or endothelial growth factor) biomarker levels were associated with MBs, while increased apolipoproteins (ApoAII, ApoCI and ApoCIII, ApoE and clusterin) and decreased AXL were associated with CAA severity in neuropathology. Ratios between inversely associated markers enhanced correlation strength and discriminated CAA status. CONCLUSIONS: Several candidate plasma biomarkers of CAA were identified in individuals with either MRI or neuropathological indicators of CAA
Pan-Multiplex (Pan-M) dataset
No full textThis dataset was constructed to train the Nimbus model for the publication "Automated classification of cellular expression in multiplexed imaging data with Nimbus". The dataset contains multiplexed images from different modalities, tissues and protein marker panels. It was constructed by a semi-automatic pipeline, where the cell types assigned by the authors of the original studies that published the data, where mapped back to their expected marker activity. In addition, for 3 FoVs of each dataset, 4 expert annotators proofread ~1.1M annotations which served as the gold-standard for assesing the algorithm. More details to the construction of the dataset can be found in the paper. The dataset consists of five subsets named codex_colon,mibi_breast,mibi_decidua,vectra_colon,vectra_pancreas, each in an individual folder. After unzipping, the data should be stored in the following folder structure to use the code provided for training and inference. To construct the binary segmentation maps used for training, you can use the code in segmentation_data_prep.py and simple_data_prep.py in the training repository
First person - Tim Petzold
Get PDFFirst Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping researchers promote themselves alongside their papers. Tim Petzold is first author on ‘ Connexin 41.8 governs timely haematopoietic stem and progenitor cell specification’, published in BiO. Tim conducted the research described in this article while a PhD student in Julien Bertrand's lab at the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland. He is now a postdoc in the lab of Holger Gerhardt at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, investigating developmental biology – previously his focus was on how blood stem cells develop and now it has shifted to how the vascular system develops
Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling
Get PDFA hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases
Early detection of acute kidney injury after congenital heart surgery - using urine proteomics to identify new biomarker candidates: a prospective clinical study
Get PDFBACKGROUND: Acute kidney injury (AKI) is a frequent complication following congenital heart surgery and is associated with increased morbidity and mortality. Early recognition is crucial, yet standard clinical biomarkers result in delayed detection. Urine, which can be collected non-invasively, offers unique insights into kidney function and systemic responses. METHODS: This prospective clinical study aimed to identify novel urinary biomarkers for the early detection of AKI, using high-accuracy proteome profiling. Patients with congenital heart disease undergoing cardiac surgery at Deutsches Herzzentrum der Charité were included in the study. Urine samples were collected at four timepoints: preoperatively and immediately postoperatively, and then again at six and 24 h post-surgery. Samples were analyzed using high-accuracy mass spectrometry. Linear models were applied to identify proteins associated with AKI. RESULTS: A total of 67 patients with a median age of two years were included, of whom thirteen (19%) developed an AKI. Fifteen potential urinary biomarkers were identified. The most promising early indicators of AKI directly after surgery across all age groups were Chitotriosidase-1 (AUC 0.79; 95% CI:0.64–0.94), Kallikrein-1 (AUC 0.76; 95% CI:0.76–0.89), and Carbonic anhydrase 3 (AUC 0.73; 95% CI:0.6–0.87). CONCLUSIONS: High-accuracy mass spectrometry urine proteome profiling enabled the identification of potential new AKI biomarkers directly after congenital heart surgery. Utilization of the urinary markers Chitotriosidase-1, Kallikrein-1 and Carbonic anhydrase 3 has the potential to enable earlier detection of patients at risk for AKI. Further validation in larger, age-stratified pediatric cohorts is required to confirm the diagnostic utility of the identified urinary biomarker candidates
Functional landscape of ubiquitin linkages couples K29-linked ubiquitylation to epigenome integrity
Get PDFLinkage-specific ubiquitin chains govern the outcome of numerous critical ubiquitin-dependent signaling processes, but their targets and functional impacts remain incompletely understood due to a paucity of tools for their specific detection and manipulation. Here, we applied a cell-based ubiquitin replacement strategy enabling targeted conditional abrogation of each of the seven lysine-based ubiquitin linkages in human cells to profile system-wide impacts of disabling formation of individual chain types. This revealed proteins and processes regulated by each of these poly-ubiquitin topologies and indispensable roles of K48-, K63- and K27-linkages in cell proliferation. We show that K29-linked ubiquitylation is strongly associated with chromosome biology, and that the H3K9me3 methyltransferase SUV39H1 is a prominent cellular target of this modification. K29-linked ubiquitylation catalyzed by TRIP12 and reversed by TRABID constitutes the essential degradation signal for SUV39H1 and is primed and extended by CullinRING ubiquitin ligase activity. Preventing K29-linkage-dependent SUV39H1 turnover deregulates H3K9me3 homeostasis but not other histone modifications. Collectively, these data resources illuminate cellular functions of linkage-specific ubiquitin chains and establish a key role of K29-linked ubiquitylation in epigenome integrity