Comparative Multi-Epitope-Ligand-Cartography reveals essential immunological alterations in Barrett's metaplasia and esophageal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Barrett's esophagus (BE) is caused by gastroesophageal reflux with consecutive mucosal inflammation, predisposing patients to the development of esophageal adenocarcinoma (EAC). We investigated changes in T cell-related mucosal combinatorial molecular protein patterns in both diseases using the novel Multi-Epitope-Ligand-Cartography, a unique robotic whole-cell imaging technology that simultaneously visualizes dozens of proteins in structurally intact tissues and correlates cellular localization of proteins with function.</p> <p>Results</p> <p>Biopsies were taken during endoscopy from BE, EAC, and normal control tissue, and proteomic microscopy was performed on 32 different epitopes. When the significance level was set to p < 0.0005 and the search depth to five antibody combinations, controls and BE can be differentiated by 63, controls and EAC by 3222, and BE from EAC by 1521 distinct protein combinations.</p> <p>For example, the number of activated apoptotic naïve and memory T cells was significantly increased only in BE, whereas the number of activated apoptotic helper and regulatory T cells was significantly elevated in BE and EAC. In contrast, the number of activated apoptotic cytotoxic T cells was significantly elevated only in EAC. Confirming different pathways in BE and EAC, the number of T lymphocytes with p53 expression and downregulation of bcl2 expression (CD3⁺p53⁺Bcl2^-NfkB^-) was significantly increased in EAC compared to BE and controls. Interestingly, the number of precursor T cells (CD7⁺) was significantly elevated only in EAC. These cells lack Bax and caspase-8, suggesting impaired apoptosis in the early stages of T cell differentiation.</p> <p>Conclusion</p> <p>Proteomic analysis showed for the first time that proteins, which are critically involved in the mucosal immune system of the esophagus, are distinctly expressed in BE and EAC, whereas others are comparably altered in both diseases, suggesting that many pathogenic events might be shared by both diseases. Topological proteomic analysis, therefore, helps us to understand the different pathogenic events in the underlying disease pathways.</p

ISLES 2022: A multi-center magnetic resonance imaging stroke lesion segmentation dataset

Magnetic resonance imaging (MRI) is an important imaging modality in stroke. Computer based automated medical image processing is increasingly finding its way into clinical routine. The Ischemic Stroke Lesion Segmentation (ISLES) challenge is a continuous effort to develop and identify benchmark methods for acute and sub-acute ischemic stroke lesion segmentation. Here we introduce an expert-annotated, multicenter MRI dataset for segmentation of acute to subacute stroke lesions (https://doi.org/10.5281/zenodo.7153326). This dataset comprises 400 multi-vendor MRI cases with high variability in stroke lesion size, quantity and location. It is split into a training dataset of n = 250 and a test dataset of n = 150. All training data is publicly available. The test dataset will be used for model validation only and will not be released to the public. This dataset serves as the foundation of the ISLES 2022 challenge (https://www.isles-challenge.org/) with the goal of finding algorithmic methods to enable the development and benchmarking of automatic, robust and accurate segmentation methods for ischemic stroke

ISLES 2022: A multi-center magnetic resonance imaging stroke lesion segmentation dataset.

Magnetic resonance imaging (MRI) is an important imaging modality in stroke. Computer based automated medical image processing is increasingly finding its way into clinical routine. The Ischemic Stroke Lesion Segmentation (ISLES) challenge is a continuous effort to develop and identify benchmark methods for acute and sub-acute ischemic stroke lesion segmentation. Here we introduce an expert-annotated, multicenter MRI dataset for segmentation of acute to subacute stroke lesions ( https://doi.org/10.5281/zenodo.7153326 ). This dataset comprises 400 multi-vendor MRI cases with high variability in stroke lesion size, quantity and location. It is split into a training dataset of n = 250 and a test dataset of n = 150. All training data is publicly available. The test dataset will be used for model validation only and will not be released to the public. This dataset serves as the foundation of the ISLES 2022 challenge ( https://www.isles-challenge.org/ ) with the goal of finding algorithmic methods to enable the development and benchmarking of automatic, robust and accurate segmentation methods for ischemic stroke

Galectin-4 Controls Intestinal Inflammation by Selective Regulation of Peripheral and Mucosal T Cell Apoptosis and Cell Cycle

Galectin-4 is a carbohydrate-binding protein belonging to the galectin family. Here we provide novel evidence that galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, galectin-4 blockade by antisense oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, galectin-4 ameliorated mucosal inflammation, induced apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and apoptosis such as inflammatory bowel disease

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Neuroendocrine Tumors: Epidemiology and analysis of prognostic factors in 399 patients - the Berlin experience

Titelblatt und Inhaltsverzeichnis Einleitung Fragestellung Methodik Ergebnisse Diskussion Zusammenfassung Literaturverzeichnis AnhangNeuroendokrine Tumoren (NET) bilden eine Tumorentität mit einer sehr geringen Inzidenz. Über deren Epidemiologie, klinischen Verlauf und Prognoseparameter wurden weltweit bisher nur wenige Daten publiziert. Ziel der vorliegenden Arbeit ist es, das große Patientenkollektiv eines gastroenterologisch- onkologischen Zentrums für NET hinsichtlich epidemiologischer und tumorbiologischer Fragestellungen zu charakterisieren und prognostische Faktoren für das Überleben der Patienten zu identifizieren. Die Krankheitsverläufe von 399 Patienten mit histologisch gesichertem NET wurden anhand eines standardisierten Fragebogens erfasst. Anschließend erfolgte die retrospektive Datenanalyse zur epidemiologischen und klinischen Charakterisierung des Patientenkollektivs mittels Statistiksoftware SPSS 10.0. Risikofaktoren für NET-assoziierten Tod wurden in einer univariaten Analyse nach Kaplan-Meier (SPSS, p<0,05) und einer multivariaten Analyse mittels Cox- Regression-Modell unter Adjustierung für Alter und Geschlecht (SAS, backward selection, p<0,05). ermittelt. Die Primärtumorlokalisationen waren wie folgt verteilt: 46,1% Vorderdarmtumoren, 37,1% Mitteldarmtumoren und 4,5% Hinterdarmtumoren. Die häufigsten organbezogenen Primartumorlokalisationen waren Pankreas (24,6%) und Ileum (26,1%). Bei 10,5% der Patienten lag ein metastasierter neuroendokriner Tumor unbekannter Primärtumorlokalisation vor. Bei 69,4% der Patienten lag bei ED eine Metastasierung vor, Hauptmanifestationsorgan war die Leber. Eine Funktionalität lag bei nur einem Drittel der Patienten bei ED vor und war ohne Einfluss auf die Prognose. Die kumulative 5-Jahres-Überlebensrate aller Patienten betrug trotz des relativ hohen Anteils fortgeschrittener Erkrankungen 78%. Die 5-JÜLR variierte in Abhängigkeit von der Primariuslokalisation (Foreguttumoren 73%/Pankreas 70% vs. Midguttumoren 86%/Jejunum/Ileum 86%) und dem Vorliegen von Metastasen bei ED (72% mit Metastasen vs. 92% ohne Nachweis von Metastasen). Als Risikofaktoren für NET-assoziierten Tod wurden in den univariaten Analysen das Vorhandensein von Metastasen bei ED (0,024), das Vorliegen einer klinischen Symptomatik bei ED (p=0,026), ein Primärtumor >2,5cm (p<0,001), eine Wachstumsfraktion >5% (p<0,001), ein fehlender immunhistochemischer Nachweis von Chromogranin A (p=0,011) und eine nicht stattgehabte operative Therapie (p<0,001) identifiziert. Als voneinander unabhängige Risikofaktoren für NET- assoziierten Tod wurden in der multivariaten Analyse eine Wachstumsfraktion >5% (p=0,01) sowie eine Primärtumorgröße >2,5cm (p<0,001) ermittelt.Neuroendocrine tumors (NET) are neoplasms with a low incidence. Until know, little is known about the epidemiology of these tumors as well as factors that may effect their long-term outcome. Due to the currently limited available data the aim of the study was to characterize a large patient cohort in terms of epidemiology and biological tumor behavior and to identify factors that may influence their prognosis. Thus, 399 patients with histological proof of neuroendocrine tumor cared for in a German referral center were investigated. Long-term survival was analyzed retrospectively, using the Kaplan-Meier-Method for univariate analysis of prognostic factors and the Cox-Regressions-Model for multivariate analysis of independent variables (age and gender adjusted, p<0.05 for each analysis). The sites of the primary tumor were 46.1% foregut origin, 37.1% midgut origin, and 4.5% hindgut origin. The most frequently localization of the primary tumor according to anatomic sites were pancreas (24.6%), and ileum (26.1%). 10.5% of the patients had a metastatic disease with an unknown primary. Metastasis at initial diagnosis occurred in 69.4%, mainly involving the liver. A hypersecretion syndrome occurred only in one third of the patients and did not effect long-term outcome. The cumulative NET-related 5-year-survival-rate was 78% despite of the highly rate of advanced neuroendocrine tumors. The 5-year-survival-rate was dependent on the site of primary tumor (foregut 73%/ pankreas 70% vs. midgut 86%/ jejunoileum 86%) and the occurrence of metastatic disease at initial diagnosis (72% with and 92% without metastasis). Metastatic disease at initial diagnosis (p=0.0024), evidence of clinical symptoms (p=0.026), size of the primary tumor >2.5cm (p5% (p=0.01), lack of Chromogranin A expression (p=0.011), and absence of any surgical procedure (p<0.001) were identified as factors associated with negative long-term outcome in the univariate analysis. As independent risk factors for NET- associated death proliferation index (Ki67) >5% (p=0.007), and size of the primary tumor >2.5cm (p<0.001) were identified